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ICH Q3D Implementation Working Group (IWG)—Training Modules

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DRUG REGULATORY AFFAIRS INTERNATIONAL

ICH Q3D Implementation Working Group (IWG)—Training Modules


ICH Q3D is a complex guideline. The overall requirement in terms of control is clear—there are defined limits for some 24 elements, and levels of the elements described must be controlled within these limits in the final drug product. Simple. The complexity comes when defining how this is achieved. The guideline provides a series of options to evaluate risk and effect control, ranging from control in each individual component based on a fixed dose for the product of 10 g (Option 1) to simply testing the final product (Option 3). A detailed description of the options and when/how these are applied as part of a risk assessment is beyond the scope of this review; the point is that there are significant challenges in applying the guideline practically solely using the guideline for that purpose. This was recognized by the ICH Expert Working Group…

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FDA´s new policy regarding grouping of supplements for CMC changes

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The US Food and Drug Administration’s (FDA) Office of Pharmaceutical Quality (OPQ) released a new document outlining how supplements can be grouped together and submitted concurrently for the same chemistry, manufacturing and controls (CMC) changes. Find out more about Policy and Procedures regarding the Review of Grouped Product Quality Supplements.

http://www.gmp-compliance.org/enews_05320_FDA%B4s-new-policy-regarding-grouping-of-supplements-for-CMC-changes_15173,Z-RAM_n.html

On April 19, 2016 the US Food and Drug Administration’s (FDA) Office of Pharmaceutical Quality (OPQ) released a new document outlining how supplements can be grouped together and submitted concurrently for the same chemistry, manufacturing and controls (CMC) changes to multiple approved new drug applications (NDAs), abbreviated new drug applications (ANDAs) and biological license applications (BLAs) submitted by the same applicant.

The agency says the goal of its new policy is to make the process more efficient and consistent when reviewing grouped supplements.The term “grouped supplements” is used to describe two or more supplements reviewed and processed using…

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EMA publishes Q A on data required for sterilized primary packaging materials used in aseptic manufacturing processes

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DRUG REGULATORY AFFAIRS INTERNATIONAL

The European Medicines Agency, EMA, recently published questions and answers on what data is required for sterilisation processes of primary packaging materials subsequently used in an aseptic manufacturing process. Read more about “What data is required for sterilisation processes of primary packaging materials subsequently used in an aseptic manufacturing process?“.

http://www.gmp-compliance.org/enews_05330_EMA-publishes-Q-A-on-data-required-for-sterilized-primary-packaging-materials-used-in-aseptic-manufacturing-processes_15303,15493,15615,Z-PKM_n.html

The European Medicines Agency, EMA, recently published questions and answers on quality of packaging materials (H+V April 2016):

“3. What data is required for sterilisation processes of primary packaging materials subsequently used in an aseptic manufacturing process?
Terminal sterilisation of the primary packaging, used subsequently during aseptic processing of the finished product, is a critical process and the sterility of the primary container is a critical quality attribute to ensure the sterility of the finished product. Both need to be assured for compliance with relevant Pharmacopoeial requirements for the finished product and product approval.

The site where sterilisation…

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ICH M7

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ICH M7



Although relatively quiet in terms of any specific regulatory activities, the last 6 months have seen a plethora of publications that are associated with the ICH M7 guideline. Prominent within these was the Special Edition of Organic Process Research & Development in November 2015. This special edition focused on mutagenic impurities, examining the challenges and also opportunities faced when seeking to implement ICH M7.(5) This was timely as it aligned with the effective date for ICH M7 of January 2016; the guideline when finalized in June 2014 having a defined implementation phase of 18 months. ICH M7 is, in general, a well-written guideline that provides a flexible and pragmatic framework by which the risk posed by mutagenic impurities can be effectively managed. The flexibility provided by the guideline and the opportunities this presents in terms of science and risk based thinking are examined in depth through a…

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PDE4 inhibitor , Sumitomo Dainippon Pharma Company

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Figure

2-[2-Methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-benzimidazol-5-yl]-1,3-benzoxazole Hemifumarate

Sumitomo Dainippon Pharma Company,

STR1

SCHEMBL2688684.png

CAS FREE FORM 1256966-65-0

Benzoxazole, 2-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-benzimidazol-5-yl]-

MF C20 H19 N3 O2, MW, 333.38 FREE FORM
NMR FOR HEMIFUMARATE

1H NMR (400 MHz, DMSO-d6)

δ 13.1 (br, 1H), 8.33 (d, J = 1.5 HZ, 1H), 8.06 (dd, J = 5.1, 1.6 Hz, 1H), 7.89 (d, J = 0.8 Hz, 1H), 7.82–7.76 (m, 2H), 7.43–7.38 (m, 2H), 6.64 (s, 1H), 4.71–4.62 (m, 1H), 4.06 (dd, J = 11.4, 4.3 Hz, 2H), 3.58 (dd, J = 11.7, 11.4 Hz, 2H), 2.67 (s, 3H), 2.47–2.36 (m, 2H), 1.90–1.86 (m, 2H).

13C NMR (100 MHz, DMSO-d6)

δ 165.92, 163.26, 153.94, 150.20, 142.94, 141.75, 136.21, 133.93, 124.94, 124.67, 120.89, 119.40, 117.70, 112.44, 110.72, 66.50, 52.67, 30.70, 14.62.
Compound 1 is a PDE4 inhibitor and is expected to improve memory impairment. In addition to the mechanism of action, 1 enhances BDNF signal transduction and induces NXF, a brain specific transcription factor, in the presence of low concentrations of BDNF. NXF induction is expected to lead to nerve regeneration and neuroprotective efficacy.
US88290352014-09-09Agent for treatment or prevention of diseases associated with activity of neurotrophic factors
 STR1
Example 11
5- (benzoxazol-2-yl) -2-methyl -1-(tetrahydropyran-4-yl) benzimidazole  eggplant flask (100 mL), 2- methyl-1- (tetrahydropyran – 4-yl) reference benzimidazole-5-carboxylic acid (example 4-3) (0.64 g, 2.46 mmol ), 2- amino-phenol (0.32 g, 2.95 mmol), and polyphosphoric acid (about 18 g) put, heated to 160 ℃, and the mixture was stirred for 17 hours. After cooling, ice was added, and the mixture was about pH 9 the liquid with concentrated aqueous ammonia (28%). Extraction with chloroform (about 50 mL X 3 times), dried over anhydrous magnesium sulfate, the crude product obtained by distilling off the solvent (0.08 g) PTLC (CHCl 3 by weight deploy purified), the title compound ( 0.002 g, 0.2% yield) was obtained as a yellow-brown semi-solid. 1H-NMR (CDCl 3 ) Deruta (Ppm): 1.88-1.92 (M, 2 H), 2.58-2.68 (M, 2 H), 2.70 (S, 3 H), 3.57-3.64 (M , 2 H), 4.21-4.25 (m , 2 H), 4.43-4.49 (m, 1 H), 7.29 (d, 1H, J = 9.2 Hz), 7.33-7.35 (m, 2 H ), 7.59-7.62 (m, 1 H ), 7.76-7.78 (m, 1 H), 8.18 (dd, 1 H, J = 8.6, 1.6 Hz), 8.57 (d, 1 H, J = 1.4 Hz).

PAPER

Abstract Image

A short and practical synthetic route of a PDE4 inhibitor (1) was established by using Pd–Cu-catalyzed C–H/C–Br coupling of benzoxazole with a heteroaryl bromide. The combination of Pd(OAc)2-Cu(OTf)2-PPh3 was found to be effective for this key step. Furthermore, telescoping methods were adopted to improve the yield and manufacturing time, and a two-step synthesis of1 was accomplished in 71% overall yield.

Direct Synthesis of a PDE4 Inhibitor by Using Pd–Cu-Catalyzed C–H/C–Br Coupling of Benzoxazole with a Heteroaryl Bromide

Process Chemistry Research and Development Laboratories, Technology Research & Development Division andDSP Cancer Institute, Sumitomo Dainippon Pharma Company, Ltd., 3-1-98 Kasugade-naka, Konohana-ku, Osaka 554-0022, Japan
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.6b00106

///////////PDE4 inhibitor , Sumitomo Dainippon Pharma Company

Cc1nc3cc(ccc3n1C2CCOCC2)c4nc5ccccc5o4


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Higenamine Hydrochloride

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Higenamine.svg

Higenamine Hydrochloride

  • 6,7-Isoquinolinediol, 1,2,3,4-tetrahydro-1-[(4-hydroxyphenyl)methyl]-, hydrochloride (9CI)
  • 6,7-Isoquinolinediol, 1,2,3,4-tetrahydro-1-[(4-hydroxyphenyl)methyl]-, hydrochloride, (±)-
  • (±)-Demethylcoclaurine hydrochloride

NDA Filed in china

A β-adrenoceptor partial agonist potentially for the treatment of coronary heart disease.


CAS No.11041-94-4 (Higenamine hydrochloride)

CAS 5843-65-2(free)

Higenamine (norcoclaurine) is a chemical compound found in a variety of plants including Nandina domestica (fruit), Aconitum carmichaelii (root), Asarum heterotropioides, Galium divaricatum (stem and vine), Annona squamosa, and Nelumbo nucifera (lotus seeds).

Legality

Higenamine, also known as norcoclaurine HCl, is legal to use within food supplements in the UK, EU, the USA and Canada. but banned use in The NCAA. Its main is within food supplements developed for weight management, also known as ‘fat burners’. However, products containing (or claiming to contain) pharmacological relevant quantities still require registration as a medicine. The regulatory boundaries for higenamine are unclear as modern formulations have not been clinically evaluated. Traditional formulations with higenamine have been used for thousands of years within Chinese medicine and come from a variety of sources including fruit and orchids. There are no studies comparing the safety of modern formulations (based on synthetic higenamine) with traditional formulations. Nevertheless, it will not be added to the EU ‘novel foods’ catalogue, which details all food supplements that require a safety assessment certificate before use.[1]

Pharmacology

Since higenamine is present in plants which have a history of use in traditional medicine, the pharmacology of this compound has attracted scientific interest. A variety of effects have been observed in in vitro studies and in animal models, but its effects in humans are unknown.

The results of a 2009 study exposed the compound as a β2 adrenergic receptor agonist.[2]

In animal models, higenamine has been demonstrated to be a β2 adrenoreceptor agonist.[2][3][4][5][6] Adrenergic receptors, or adrenoceptors, belong to the class of G protein–coupled receptors, and are the most prominent receptors in the adipose membrane, besides also being expressed in skeletal muscle tissue. These adipose membrane receptors are classified as either α or β adrenoceptors. Although these adrenoceptors share the same messenger, cyclic adenosine monophosphate (cAMP), the specific transduction pathway depends on the receptor type (α or β). Higenamine partly exerts its actions by the activation of an enzyme,adenylate cyclase, responsible for boosting the cellular concentrations of the adrenergic second messenger, cAMP.[7]

In a rodent model, it was found that higenamine produced cardiotonic, vascular relaxation, and bronchodilator effects.[8][9] In particular, higenamine, via a beta-adrenoceptor mechanism, induced relaxation in rat corpus cavernosum, leading to improved vasodilation and erectile function.

Related to improved vasodilatory signals, higenamine has been shown in animal models to possess antiplatelet and antithrombotic activity via a cAMP-dependent pathway, suggesting higenamine may contribute to enhanced vasodilation and arterial integrity.[2][7][9][10]

Toxicity

Regarding toxicity, researchers have suggested that the levels of higenamine reported in food consumption (estimated 47.5 mg in a 9-ounce serving of Lotus) would be comparable to the amount used in food supplements.[citation needed] Higenamine is a beta-adrenergic agonist which has effects on the function of trachea and heart muscles.[11][12]During a study of acute toxicity, mice were orally administered the compound at a dose of 2 g per kg of bodyweight. No mice died during the study.[13] higenamine is one of the main chemicals in a plant called aconite. Aconite has been shown to cause serious heart-related side effects including arrhythmias and even death. in some sources of HIGENAMINE from certain plants that have Aconite

PAPER

Chemical & Pharmaceutical Bulletin (1978), 26(7), 2284-5

https://www.jstage.jst.go.jp/article/cpb1958/26/7/26_7_2284/_pdf

PATENT

CN 103554022

http://google.com/patents/CN103554022B?cl=en

Example 1:

[0024] to the S-necked flask 200mL of anhydrous ammonia clever four furans, lOg instrument crumbs, olive mix was added 0. 5g ship, continue to embrace the mix was added 10 minutes after which 2 drops of 1,2-B burning desert, Continue mixing until the reaction mixture embrace color disappeared, the reaction was cooled to square ° C, and slowly mixed solution thereto 31. 6g4- methoxy Desert Festival and 50mL tetraammine clever furans dropped, about 60min addition was complete, the reaction fluid continues to cool to -65 ° C, to which was slowly dropping 20 percent, 7-dimethoxy-3,4-diamine different wow beep and a mixed solution of ammonia lOOmL four clever furans, the addition was complete continue to maintain – 65 ° C for 2 hours after the embrace slowly warmed 0 ° C, maintaining the internal temperature of 100 ° C 〇 blood slowly added to the reaction mixture, the addition was completed adding 200 blood continues to embrace mixed with ethyl acetate after 0.5 hours, allowed to stand liquid separation, organic phase was separated, dried over anhydrous sulfate steel, concentrated to afford 6, 7-dimethoxy -l- (4- methoxy section yl) -1,2, 3, 4-isopropyl tetraammine wow toot 24. 9g, a yield of 76.1%.

[00 Qiao] to the reaction flask prepared above 6, 7-dimethoxy -l- (4- methoxybenzyl) -1,2, 3, 4 tetraammine different wow beep 24. 9g , 47% aqueous ammonia desert 200 blood acid heated to 130 ° C reflux of cooled to room temperature, precipitation of large amount of solid, filtered higenamine ammonia salt desert, the solid was added 1. of water and continue to add 50 Blood mixed with ammonia football ground, filtered higenamine to higenamine was added lL4mol / L aqueous hydrochloric acid, 80 ° C heat to embrace mixed, cooled to 25 ° C filtration and drying to obtain a final product hydrochloric acid higenamine 11. 7g, a yield of 73.3%.

STR1

References

  1.  http://ec.europa.eu/food/food/biotechnology/novelfood/novel_food_catalogue_en.htm
  2.  Tsukiyama, M; Ueki, T; Yasuda, Y; Kikuchi, H; Akaishi, T; Okumura, H; Abe, K (2009). “Beta2-adrenoceptor-mediated tracheal relaxation induced by higenamine from Nandina domestica Thunberg”. Planta Medica 75 (13): 1393–9. doi:10.1055/s-0029-1185743. PMID 19468973.
  3.  Kashiwada, Y; Aoshima, A; Ikeshiro, Y; Chen, YP; Furukawa, H; Itoigawa, M; Fujioka, T; Mihashi, K; et al. (2005). “Anti-HIV benzylisoquinoline alkaloids and flavonoids from the leaves of Nelumbo nucifera, and structure-activity correlations with related alkaloids”.Bioorganic & Medicinal Chemistry 13 (2): 443–8. doi:10.1016/j.bmc.2004.10.020.PMID 15598565.
  4.  Kimura, I; Chui, LH; Fujitani, K; Kikuchi, T; Kimura, M (1989). “Inotropic effects of (+/-)-higenamine and its chemically related components, (+)-R-coclaurine and (+)-S-reticuline, contained in the traditional sino-Japanese medicines “bushi” and “shin-i” in isolated guinea pig papillary muscle”. Japanese journal of pharmacology 50 (1): 75–8.doi:10.1254/jjp.50.75. PMID 2724702.
  5.  Kang, YJ; Lee, YS; Lee, GW; Lee, DH; Ryu, JC; Yun-Choi, HS; Chang, KC (1999). “Inhibition of activation of nuclear factor kappaB is responsible for inhibition of inducible nitric oxide synthase expression by higenamine, an active component of aconite root”. The Journal of Pharmacology and Experimental Therapeutics 291 (1): 314–20.PMID 10490919.
  6.  Yun-Choi, HS; Pyo, MK; Park, KM; Chang, KC; Lee, DH (2001). “Anti-thrombotic effects of higenamine”. Planta Medica 67 (7): 619–22. doi:10.1055/s-2001-17361.PMID 11582538.
  7.  Kam, SC; Do, JM; Choi, JH; Jeon, BT; Roh, GS; Chang, KC; Hyun, JS (2012). “The relaxation effect and mechanism of action of higenamine in the rat corpus cavernosum”.International Journal of Impotence Research 24 (2): 77–83. doi:10.1038/ijir.2011.48.PMID 21956762.
  8.  Bai, G; Yang, Y; Shi, Q; Liu, Z; Zhang, Q; Zhu, YY (2008). “Identification of higenamine in Radix Aconiti Lateralis Preparata as a beta2-adrenergic receptor agonist1”. Acta pharmacologica Sinica 29 (10): 1187–94. doi:10.1111/j.1745-7254.2008.00859.x.PMID 18817623.
  9.  Pyo, MK; Lee, DH; Kim, DH; Lee, JH; Moon, JC; Chang, KC; Yun-Choi, HS (2008). “Enantioselective synthesis of (R)-(+)- and (S)-(-)-higenamine and their analogues with effects on platelet aggregation and experimental animal model of disseminated intravascular coagulation”. Bioorganic & Medicinal Chemistry Letters 18 (14): 4110–4.doi:10.1016/j.bmcl.2008.05.094. PMID 18556200.
  10.  Liu, W; Sato, Y; Hosoda, Y; Hirasawa, K; Hanai, H (2000). “Effects of higenamine on regulation of ion transport in guinea pig distal colon”. Japanese journal of pharmacology 84(3): 244–51. doi:10.1254/jjp.84.244. PMID 11138724.
  11.  Wong, KK; Lo, CF; Chen, CM (1997). “Endothelium-dependent higenamine-induced aortic relaxation in isolated rat aorta”. Planta Medica 63 (2): 130–2. doi:10.1055/s-2006-957628. PMID 9140225.
  12.  Ueki, T; Akaishi, T; Okumura, H; Morioka, T; Abe, K (2011). “Biphasic tracheal relaxation induced by higenamine and nantenine from Nandina domestica Thunberg”. Journal of pharmacological sciences 115 (2): 254–7. doi:10.1254/jphs.10251sc. PMID 21282929.
  13. Lo, CF; Chen, CM (1997). “Acute toxicity of higenamine in mice”. Planta Medica 63 (1): 95–6. doi:10.1055/s-2006-957619. PMID 9063102.

banned in ncaa https://www.ncaa.org/sites/default/files/2015-16%20NCAA%20Banned%20Drugs.pdf

CN1539823A * Oct 27, 2003 Oct 27, 2004 中国医学科学院药物研究所 Method for preparing new demethyl conclaurine and medinal salt
CN1764647A * Mar 23, 2004 Apr 26, 2006 埃科特莱茵药品有限公司 Tetrahydroisoquinolyl acetamide derivatives for use as orexin receptor antagonists
CN103351338A * Jun 17, 2013 Oct 16, 2013 张家港威胜生物医药有限公司 Simple preparation process of higenamine hydrochloride
US20060030586 * Sep 27, 2004 Feb 9, 2006 Education Center Of Traditional Chinese Medicine Co. Method and health food for preventing and/or alleviating psychiatric disorder, and/or for effectuating sedation
WO2011038169A2 * Sep 24, 2010 Mar 31, 2011 Mallinckrodt Inc. One-pot preparation of hexahydroisoquinolines from amides
Higenamine
Higenamine.svg
Names
IUPAC name
1-[(4-Hydroxyphenyl)methyl]-1,2,3,4-tetrahydroisoquinoline-6,7-diol
Other names
norcoclaurine, demethylcoclaurine
Identifiers
5843-65-2 Yes
106032-53-5 (R) 
22672-77-1 (S) 
ChEBI CHEBI:18418 Yes
ChEMBL ChEMBL19344 Yes
ChemSpider 102800 Yes
Jmol 3D model Interactive image
KEGG C06346 Yes
MeSH higenamine
PubChem 114840
Properties
C16H17NO3
Molar mass 271.32 g·mol−1

/////


Filed under: Uncategorized Tagged: Higenamine Hydrochloride

EU GMP Annex 1 Revision 2016 – what does the pharmaceutical industry expect?

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Dr Friedrich Haefele, Vice President Fill & Finish Biopharma at Boehringer Ingelheim

Dr Friedrich Haefele, Vice President Fill & Finish Biopharma at Boehringer Ingelheim talked in his keynote speech at the Pharma Congress 2016 about the revision of Annex 1 of the EU GMP Guide. Read here what the pharmaceutical industry expects form the new Annex 1.

http://www.gmp-compliance.org/enews_05326_EU-GMP-Annex-1-Revision-2016—what-does-the-pharmaceutical-industry-expect_15160,15266,15265,15432,Z-PEM_n.html

Europe’s biggest Pharma Congress of its kind took place in Düsseldorf on 12 and 13 April. With more than 1000 participants, 90 exhibitors and 10 GMP conferences this Congress 2016 has been the biggest since the first one 18 years ago. 50 lectures, almost exclusively case studies from pharmacuetical companies such as Pfizer, Novartis, Boehringer Ingelheim and many more were discussed. Special attention was paid to the keynotes at the beginning of each congress day.

Dr Friedrich Haefele, Vice President Fill & Finish Biopharma at Boehringer Ingelheim talked in his keynote…

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WHO issues revised Guideline on HVAC Systems

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The World Health Organization (WHO) recently issued a guideline for commenting which describes the requirements for HVAC systems for the manufacture of non-sterile forms. As most guidelines on this topic address the requirements for sterile dosage forms, the previous version was gladly accepted by industry. Learn more about the revised guideline on HVAC systems.

http://www.gmp-compliance.org/enews_05358_WHO-issues-revised-Guideline-on-HVAC-Systems_15160,15221,15661,15612,Z-PEM_n.html

The World Health Organization (WHO) recently issued a guideline for commenting which describes the requirements for HVAC systems used for the manufacture of non-sterile dosage forms. As most guidelines on this topic address the requirements for sterile forms, the previous version (TRS 961, Annex 1) from 2011 was gladly accepted by industry. Mentioned are non-sterile dosage forms as tablets, capsules, liquids or ointments, but also for the final steps in the manufacture of APIs. The WHO guideline means to provide guidance specifically for the areas design, installation, qualification and maintenance of ventilation systems. For the manufacture of…

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[18F]AMG 580

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STR1

[18F]AMG 580

CAS 1879904-74-1
MF C26 H24 F N5 O3

NOTE………CAS OF AMG 580 IS 1227067-71-1, WITHOUT 18F

AMG 580 [1-(4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)-2-fluoropropan-1-one],

STR1

Phosphodiesterase 10A (PDE10A) inhibitors have therapeutic potential for the treatment of psychiatric and neurologic disorders, such as schizophrenia and Huntington’s disease. One of the key requirements for successful central nervous system drug development is to demonstrate target coverage of therapeutic candidates in brain for lead optimization in the drug discovery phase and for assisting dose selection in clinical development. Therefore, we identified AMG 580 [1-(4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)-2-fluoropropan-1-one], a novel, selective small-molecule antagonist with subnanomolar affinity for rat, primate, and human PDE10A. We showed that AMG 580 is suitable as a tracer for lead optimization to determine target coverage by novel PDE10A inhibitors using triple-stage quadrupole liquid chromatography–tandem mass spectrometry technology. [3H]AMG 580 bound with high affinity in a specific and saturable manner to both striatal homogenates and brain slices from rats, baboons, and human in vitro. Moreover, [18F]AMG 580 demonstrated prominent uptake by positron emission tomography in rats, suggesting that radiolabeled AMG 580 may be suitable for further development as a noninvasive radiotracer for target coverage measurements in clinical studies. These results indicate that AMG 580 is a potential imaging biomarker for mapping PDE10A distribution and ensuring target coverage by therapeutic PDE10A inhibitors in clinical studies.

PAPER

Abstract Image

We report the discovery of PDE10A PET tracer AMG 580 developed to support proof of concept studies with PDE10A inhibitors in the clinic. To find a tracer with higher binding potential (BPND) in NHP than our previously reported tracer 1, we implemented a surface plasmon resonance assay to measure the binding off-rate to identify candidates with slower washout rate in vivo. Five candidates (26) from two structurally distinct scaffolds were identified that possessed both the in vitro characteristics that would favor central penetration and the structural features necessary for PET isotope radiolabeling. Two cinnolines (2, 3) and one keto-benzimidazole (5) exhibited PDE10A target specificity and brain uptake comparable to or better than 1 in the in vivo LC–MS/MS kinetics distribution study in SD rats. In NHP PET imaging study, [18F]-5 produced a significantly improved BPND of 3.1 and was nominated as PDE10A PET tracer clinical candidate for further studies.

Discovery of Phosphodiesterase 10A (PDE10A) PET Tracer AMG 580 to Support Clinical Studies

Department of Medicinal Chemistry, Department of Pharmacokinetics and Drug Metabolism, §Department of Neuroscience, and ΔDepartment of Early Development, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 93012-1799, United States
Department of Neuroscience and ±Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, California 94080, United States
Department of Molecular Structure and Characterization, Amgen Inc., 360 Binney Street, Cambridge, Massachusetts 02142, United States
ACS Med. Chem. Lett., Article ASAP
DOI: 10.1021/acsmedchemlett.6b00185
*Phone: 805-313-5300. E-mail: ehu@amgen.com.
STR1

PATENT FOR AMG 580

WO 2010057121

https://www.google.com/patents/WO2010057121A1?cl=en

PAPER

Nuclear Medicine and Biology (2015), 42(8), 654-663.

http://www.sciencedirect.com/science/article/pii/S0969805115000724

Phosphodiesterase 10A (PDE10A) is an intracellular enzyme responsible for the breakdown of cyclic nucleotides which are important second messengers for neurotransmission. Inhibition of PDE10A has been identified as a potential target for treatment of various neuropsychiatric disorders. To assist drug development, we have identified a selective PDE10A positron emission tomography (PET) tracer, AMG 580. We describe here the radiosynthesis of [18 F]AMG 580 and in vitro and in vivo characterization results.

AMG 580 has an in vitro KD of 71.9 pM. Autoradiography showed specific uptake in striatum. Mean activity of 121 ± 18 MBq was used in PET studies. In Rhesus, the baseline BPND for putamen and caudate was 3.38 and 2.34, respectively, via 2TC, and 3.16, 2.34 via Logan, and 2.92, and 2.01 via SRTM. A dose dependent decrease of BPNDwas observed by the pre-treatment with a PDE10A inhibitor. In baboons, 0.24 mg/kg dose of AMG 580 resulted in about 70% decrease of BPND. The in vivo KD of [18 F]AMG 580 was estimated to be around 0.44 nM in baboons.

Conclusion

[18 F]AMG 580 is a selective and potent PDE10A PET tracer with excellent specific striatal binding in non-human primates. It warrants further evaluation in humans.

REFERNCES

http://jpet.aspetjournals.org/content/352/2/327.full

///Phosphodiesterasetracer,  receptor occupancy,  positron emission tomographyradiotracer,  brain penetrationAMG 580, Phosphodiesterase 10A, PDE10A, PET Tracer, [18F]AMG 580


Filed under: Uncategorized Tagged: AMG 580, brain penetration, PDE10A, PET Tracer, Phosphodiesterase, Phosphodiesterase 10A, positron emission tomography, radiotracer, receptor occupancy, tracer, [18F]AMG 580

[F-18](2S,4S)-4-(3-Fluoropropyl)glutamine

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STR1

[F-18](2S,4S)-4-(3-Fluoropropyl)glutamine

CAS 1196963-79-7

MF C8 H15 F N2 O3
Heptanoic acid, 2-amino-4-(aminocarbonyl)-7-(fluoro-18F)-, (2S,4S)-
[18F](2S,4S)-4-FPGln

[18F](2S,4S)-4-(3-fluoropropyl)glutamine, 4

The early diagnosis of malignant tumors plays a very important role in the survival prognosis of cancer patients. In this non-invasive diagnosis, diagnostic imaging procedures are an important tool. In the last few years has mainly PET technology (P ositronen- E mission- Tomographie) proved to be particularly useful. The sensitivity and specificity of PET technology depends significantly on the used signal-emitting substance (tracer) and their distribution in the body from. In the search for suitable tracers one tries to take advantage of certain properties of tumors differ, the tumor tissue from healthy, surrounding tissue. The preferred commercially used isotope which finds application for PET, 18 F 18 F represents by its short half-life of less than 2 hours special requirements for the preparation of suitable tracer. Complex, long synthetic routes and purifications are with this isotope is not possible, because otherwise a significant portion of the radioactivity of the isotope has already decayed before the tracer can be used for diagnosis. It is therefore often not possible to established synthetic routes for non-radioactive fluorination to be applied to the synthesis of18 F-tracer. Furthermore, the high specific activity of 18 F (80 GBq / nmol) at very low substance amounts of [18 F] fluoride for the tracer synthesis, which in turn an extreme excess of precursor-related and the success of a non-radioactive fluorination based Radio synthetic strategy designed unpredictable

FDG ([18 F] F 2 luoro d esoxy lukose g) -PET is a widely accepted and popular tool in the diagnosis and other clinical tracking of tumor diseases. Malignant tumors compete with the host organism to glucose supply to the nutrient supply (Warburg O. About the metabolism of carcinoma cell Biochem;.. Kellof G. Progress and Promise of FDG PET Imaging for Cancer Patient Management and Oncologic Drug Development Clin Cancer Res 2005;.. 11 (8): 2785-2807) where tumor cells compared to surrounding cells of normal tissue usually an increased glucose metabolism. This is used when using fluorodeoxyglucose (FDG), a glucose derivative, which is amplified transported into the cells, but there included metabolically after phosphorylation as FDG-6-phosphate (“Warburg effect”). 18 F-labeled FDG is Therefore, an effective tracer for the detection of tumors in patients using PET technology. Imaging were looking for new PET tracers in recent years increasingly amino acids for 18 F PET used (eg (review): Eur J Nucl Med Mol Imaging 2002 May; 29 (5):.. 681-90). In this case, some of the 18 F-labeled amino acids for the measurement of the speed rate of protein synthesis, the most useful derivatives but for the direct measurement of the cellular uptake in the tumor. Known 18 F-labeled amino acids are, for example, from tyrosine, phenylalanine, proline, aspartic and unnatural amino acids derived (eg J. Nucl Med 1991; 32:.. 1338-1346, J Nucl Med 1996; 37: 320-325, J Nucl Med 2001; 42: 752-754 J Nucl Med and 1999, 40: 331-338).. Glutamic acid and glutamine than 18 F-labeled derivatives not known, whereas non-radioactive fluorinated glutamine and glutamic acid derivatives are well known; Thus, for Example those which at γ-position (for Ex (review):Amino Acids (2003) April; 24 (3):… 245-61).. or at β-position (e.g. ExTetrahedron. Lett. .; 30; 14; 1989, 1799-1802, J. Org Chem .; 54; 2; 1989, 498-500, Tetrahedron: Asymmetry, 12, 9; 2001; 1303-1312) havefluorine..

Of glutamic acid having the chemical functionalities protecting groups in β and γ position or a leaving group, has already been reported in the past. So was informed of glutamate as mesylate or bromide in γ-position whose acid and amine functions were provided with ester or Z-protecting groups (J. Chem Soc Perkin Trans. 1;.. 1986, 1323-1328) or, for example, of γ-chloro-glutamic acid without protecting groups(Synthesis, (1973); 44-46). About similar derivatives, but where the leaving group is positioned in β-position has also been reported on several occasions. Z Ex. Chem. Pharm. Bull .; 17; 5; (1969); 879-885,J.Gen.Chem.USSR (Engl.Transl.); 38; (1968); 1645-1648, Tetrahedron Lett .; 27; 19; (1986); 2143-2144, Chem. Pharm. Bull .; EN; 17; 5; 1969;873-878, patent FR 1461184 , Patent JP 13142 .)

The current PET tracers, which are used for tumor diagnosis have some undisputed disadvantages: in FDG accumulates preferably in those cells with increased glucose metabolism on, but there are also other pathological and physiological conditions of increased glucose metabolism in the cells involved and tissues, eg, Ex. of infection or wound healing (summarized in J. Nucl. Med. Technol. (2005), 33, 145-155). It is still often difficult to decide whether a detected by FDG-PET lesion actually neoplastic origin or due to other physiological or pathological state of the tissue. Overall, the diagnostic activity by FDG-PET in oncology has a sensitivity of 84% and a specificity of 88% to(Gambhir et al., ” A tabulated summary of the FDG PET literature “J. Nucl. Med. 2001, 42, 1- 93S). Tumors in the brain can be represented very difficult in healthy brain tissue, for example, by the high accumulation of FDG.

The previously known 18 F-labeled amino acid derivatives are in some cases well suited to detect tumors in the brain ((review): Eur J Nucl Med Mol Imaging 2002 May; 29 (5):. 681-90), but they can in other tumors do not compete with the imaging properties of the “gold standard” [18 F] 2-FDG. The metabolic accumulation and retention of previously F-18 labeled amino acids in tumorous tissue is usually lower than for FDG. Moreover, the accessibility of isomerically pure F-18-labeled non-aromatic amino acids is chemically very demanding.

Similar to glucose increased metabolism in proliferating tumor cells has been described (Medina, J Nutr 1131: 2539S-2542S, 2001; Souba, Ann Surg 218:. 715-728, 1993) for glutamic acid and glutamine. The increased rate of protein and nucleic acid synthesis and energy production per se be accepted as reasons for increased Glutaminkonsum of tumor cells. The synthesis of the corresponding C-11 and C-14 labeled with the natural substrate thus identical compounds, has already been described in the literature (eg. Ex.Antoni, enzymes Catalyzed Synthesis of L- [4-C-11] Aspartate and L – [5-C-11] Glutamate J. Labelled Compd Radiopharm 44; (4) 2001: 287-294) and Buchanan, The biosynthesis of showdomycin: studies with stable isotopes and the determination of principal precursor J….. Chem. Soc. Chem. Commun .; EN; 22; 1984, 1515-1517). First indications with the C-11 labeled compound indicate no significant tumor accumulation.

Although the growth and proliferation of most tumors is fueled by glucose, some tumors are more likely to metabolize glutamine. In particular, tumor cells with the upregulated c-Myc gene are generally reprogrammed to utilize glutamine. We have developed new 3-fluoropropyl analogs of glutamine, namely [(18)F](2S,4R)- and [(18)F](2S,4S)-4-(3-fluoropropyl)glutamine, 3 and 4, to be used as probes for studying glutamine metabolism in these tumor cells. Optically pure isomers labeled with (18)F and (19)F (2S,4S) and (2S,4R)-4-(3-fluoropropyl)glutamine were synthesized via different routes and isolated in high radiochemical purity (≥95%). Cell uptake studies of both isomers showed that they were taken up efficiently by 9L tumor cells with a steady increase over a time frame of 120 min. At 120 min, their uptake was approximately two times higher than that of l-[(3)H]glutamine ([(3)H]Gln). These in vitro cell uptake studies suggested that the new probes are potential tumor imaging agents. Yet, the lower chemical yield of the precursor for 3, as well as the low radiochemical yield for 3, limits the availability of [(18)F](2S,4R)-4-(3-fluoropropyl)glutamine, 3. We, therefore, focused on [(18)F](2S,4S)-4-(3-fluoropropyl)glutamine, 4. The in vitro cell uptake studies suggested that the new probe, [(18)F](2S,4S)-4-(3-fluoropropyl)glutamine, 4, is most sensitive to the LAT transport system, followed by System N and ASC transporters. A dual-isotope experiment using l-[(3)H]glutamine and the new probe showed that the uptake of [(3)H]Gln into 9L cells was highly associated with macromolecules (>90%), whereas the [(18)F](2S,4S)-4-(3-fluoropropyl)glutamine, 4, was not (<10%). This suggests a different mechanism of retention. In vivo PET imaging studies demonstrated tumor-specific uptake in rats bearing 9L xenographs with an excellent tumor to muscle ratio (maximum of ∼8 at 40 min). [(18)F](2S,4S)-4-(3-fluoropropyl)glutamine, 4, may be useful for testing tumors that may metabolize glutamine related amino acids.

STR1

[18F](2S,4S)-4-(3-Fluoropropyl)glutamine as a Tumor Imaging Agent

http://pubs.acs.org/doi/full/10.1021/mp500236y

Departments of Radiology and Pharmacology, University of Pennsylvania, 3700 Market Street, Philadelphia, Pennsylvania 19104, United States
Mol. Pharmaceutics, 2014, 11 (11), pp 3852–3866
DOI: 10.1021/mp500236y
Publication Date (Web): August 05, 2014
Copyright © 2014 American Chemical Society
*Email: kunghf@sunmac.spect.upenn.edu. Phone: 215-662-3096. Fax: 215-349-5035.

ACS AuthorChoice – This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.

This article is part of the Positron Emission Tomography: State of the Art special issue.

Abstract

Abstract Image

Although the growth and proliferation of most tumors is fueled by glucose, some tumors are more likely to metabolize glutamine. In particular, tumor cells with the upregulated c-Myc gene are generally reprogrammed to utilize glutamine. We have developed new 3-fluoropropyl analogs of glutamine, namely [18F](2S,4R)- and [18F](2S,4S)-4-(3-fluoropropyl)glutamine, 3 and 4, to be used as probes for studying glutamine metabolism in these tumor cells. Optically pure isomers labeled with 18F and 19F (2S,4S) and (2S,4R)-4-(3-fluoropropyl)glutamine were synthesized via different routes and isolated in high radiochemical purity (≥95%). Cell uptake studies of both isomers showed that they were taken up efficiently by 9L tumor cells with a steady increase over a time frame of 120 min. At 120 min, their uptake was approximately two times higher than that of l-[3H]glutamine ([3H]Gln). These in vitro cell uptake studies suggested that the new probes are potential tumor imaging agents. Yet, the lower chemical yield of the precursor for 3, as well as the low radiochemical yield for 3, limits the availability of [18F](2S,4R)-4-(3-fluoropropyl)glutamine, 3. We, therefore, focused on [18F](2S,4S)-4-(3-fluoropropyl)glutamine, 4. The in vitro cell uptake studies suggested that the new probe, [18F](2S,4S)-4-(3-fluoropropyl)glutamine, 4, is most sensitive to the LAT transport system, followed by System N and ASC transporters. A dual-isotope experiment using l-[3H]glutamine and the new probe showed that the uptake of [3H]Gln into 9L cells was highly associated with macromolecules (>90%), whereas the [18F](2S,4S)-4-(3-fluoropropyl)glutamine, 4, was not (<10%). This suggests a different mechanism of retention. In vivo PET imaging studies demonstrated tumor-specific uptake in rats bearing 9L xenographs with an excellent tumor to muscle ratio (maximum of ∼8 at 40 min). [18F](2S,4S)-4-(3-fluoropropyl)glutamine, 4, may be useful for testing tumors that may metabolize glutamine related amino acids.

PATENT

US 20100290991

http://www.google.com/patents/US20100290991

Figure US20100290991A1-20101118-C00029

PATENT

WO 2009141091

https://patentscope.wipo.int/search/ko/detail.jsf?docId=WO2009141091&recNum=70&maxRec=287&office=&prevFilter=%26fq%3DOF%3ACU&sortOption=Relevance&queryString=&tab=PCTDescription

PATENT

http://www.google.co.ug/patents/EP2123621A1?cl=en

REFERENCES

https://www.researchgate.net/publication/264538736_F-182S4S-4-3-Fluoropropylglutamine_as_a_Tumor_Imaging_Agent

Molecular Pharmaceutics (2014), 11(11), 3852-3866

EP1923382A1 * 18 Nov 2006 21 May 2008 Bayer Schering Pharma Aktiengesellschaft [18F] labelled L-glutamic acid, [18F] labelled glutamine, their derivatives, their use and processes for their preparation
FR1461184A Title not available
JPS58113142A Title not available
WO2008052788A1 * 30 Oct 2007 8 May 2008 Bayer Schering Pharma Aktiengesellschaft [f-18]-labeled l-glutamic acid, [f-18]-labeled l-glutamine, derivatives thereof and use thereof and processes for their preparation

////////


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Дапипразол Dapiprazole

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Dapiprazole.svg

Dapiprazole

CAS 72822-12-9

HCL SALT 72822-13-0

5,6,7,8-Tetrahydro-3-(2-(4-(O-tolyl)-1-piperazinyl)ethyl)-S-triazolo(4,3-a)pyridine

Dapiprazole (Rev-Eyes) is an alpha blocker. It is used to reverse mydriasis after eye examination.[1]

Used in the treatment of iatrogenically induced mydriasis produced by adrenergic (phenylephrine) or parasympatholytic (tropicamide) agents used in certain eye examinations.

Dapiprazole is an alpha-adrenergic blocking agent. It produces miosis by blocking the alpha-adrenergic receptors on the dilator muscle of the iris. Dapiprazole produces no significant action on ciliary muscle contraction and thus, there are no changes in the depth of the anterior chamber of the thickness of the lens. It does not alter the IOP either in normal eyes or in eyes with elevated IOP. The rate of pupillary constriction may be slightly slower in clients with brown irises than in clients with blue or green irises.

Dapiprazole acts through blocking the alpha1-adrenergic receptors in smooth muscle. It produces miosis through an effect on the dilator muscle of the iris and does not have any significant activity on ciliary muscle contraction and, therefore does not induce a significant change in the anterior chamber depth or the thickness of the lens.

Oral LD50 is 1189-2100 mg/kg in mice, rats and rabbits.

Brief background information

Salt ATC formula MM CASE
N05AX
S01EX02
C19H27N5 325.46 g / mol 72822-12-9
monogïdroxlorïd N05AX
S01EX02
C19H27N5 · HCl 361.92 g / mol 72822-13-0

Application

  • antipsihoticheskoe means
  • in the treatment of glaucoma

Classes substance

  • Piperazinы
    • 1,2,4-triazolo [4,3-a] piridinы

Synthesis

STR1

 

 

Синтез a)

Scheme illustration:By cyclization of O-methylvalerolactam (I) with 3-(4-o-tolyl-1-piperazinyl) propionic acid hydrazide (II) in refluxing xylene, followed by a treatment with ethanolic HCl.

FR 2423221; GB 2020269; JP 54157576; NL 7902489; US 4252721

 

 

Acylation of (1-methylcyclopropyl)guanidine (IV) with 3-bromo-5-chlorothiophene-2-sulfonyl chloride (III) under Schotten-Baumann conditions afforded the sulfonyl guanidine (V). This was cyclized to the desired thienothiadiazine upon treatment with Cs2CO3 and Cu2O in boiling butanol.

 

In a different method, (1-methylcyclopropyl)guanidine (I) is acylated by 3-bromo-5-chlorothiophene-2-sulfonyl chloride (II) to produce the sulfonyl guanidine (III). Intramolecular cyclization of (III) in the presence of Cu2O and Cs2CO3 leads to the title thienothiadiazine derivative. Similarly, acylation of guanidine (I) with 3,5-dichlorothiophene-2-sulfonyl chloride (IV) provides sulfonyl guanidine (V), which is then cyclized in the presence of Cu2O and Cs2CO3.

 

In an alternative method, sulfonylation of N-isopropylguanidine (V) with 2,5-dichlorothiophene-3-sulfonyl chloride (IV) produced the sulfonyl guanidine (VI). This was then cyclized to the title compound by treatment with copper bronze and potassium carbonate in boiling DMF……..WO 0102410

Trade names

country Tradename Manufacturer
Germany Remidrial winegrower
Italy Glamidolo Angelini, 1987
Ukraine no no

Formulations

  • eyedrops 50 mg / 10 ml (5%) (hydrochloride)

References

  • DE 2 915 318 (Angelini; appl. 14.4.1979; I-prior. 18.4.1978).
  • US 4 307 095 (Angelini; 22.12.1981; prior. 29.3.1979, 29.8.1980; I-prior. 18.4.1978).
  • US 4 307 096 (Angelini; 22.12.1981; prior. 29.3.1979, 29.8.1980; I-prior. 18.4.1978).
  • US 4 325 952 (Angelini; 20.4.1982; prior. 29.3.1979, 29.8.1980; I-prior. 18.4.1978).
  • BE 877 161 (Angelini; appl. 21.6.1979).

References

  1. Doughty, Michael J.; Lyle, William M. (May 1992). “A Review of the Clinical Pharmacokinetics of Pilocarpine, Moxisylyte (Thymoxamine), and Dapiprazole in the Reversal of Diagnostic Pupillary Dilation”. Optometry & Vision Science 69 (5).
  2. US 4 307 096 (Angelini; 22.12.1981; prior. 29.3.1979, 29.8.1980; I-prior. 18.4.1978).
  3.  US 4 325 952 (Angelini; 20.4.1982; prior. 29.3.1979, 29.8.1980; I-prior. 18.4.1978).
  4. BE 877 161 (Angelini; appl. 21.6.1979).
  5. DE 2 915 318 (Angelini; appl. 14.4.1979; I-prior. 18.4.1978).
  6. US 4 307 095 (Angelini; 22.12.1981; prior. 29.3.1979, 29.8.1980; I-prior. 18.4.1978).

Structural formula

UV- Spectrum

Conditions : Concentration – 1 mg / 100 ml
The solvent designation schedule methanol
water
0.1М HCl
0.1M NaOH
maximum absorption 235 nm 235 nm 234 nm There
decay
212 179 172
e 7650 6450 6200

IR – spectrum

Wavelength (μm)
Wave number (cm -1 )

 STR1
STR1

References

  • UV and IR Spectra. H.-W. Dibbern, R.M. Muller, E. Wirbitzki, 2002 ECV
  • NIST/EPA/NIH Mass Spectral Library 2008
  • Handbook of Organic Compounds. NIR, IR, Raman, and UV-Vis Spectra Featuring Polymers and Surfactants, Jr., Jerry Workman. Academic Press, 2000.
  • Handbook of ultraviolet and visible absorption spectra of organic compounds, K. Hirayama. Plenum Press Data Division, 1967.

 

Dapiprazole
Dapiprazole.svg
Systematic (IUPAC) name
3-{2-[4-(2-methylphenyl)piperazin-1-yl]ethyl}-5,6,7,8-
tetrahydro-[1,2,4]triazolo[4,5-a]pyridine
Clinical data
AHFS/Drugs.com Consumer Drug Information
MedlinePlus a601043
Pregnancy
category
  • B
Routes of
administration
Topical (eye drops)
Legal status
Legal status
  • ℞ (Prescription only)
Pharmacokinetic data
Bioavailability Negligible when administered topically
Identifiers
CAS Number 72822-12-9 Yes
ATC code S01EX02 (WHO)
PubChem CID 3033538
IUPHAR/BPS 7155
DrugBank DB00298 Yes
ChemSpider 2298190 Yes
UNII 5RNZ8GJO7K Yes
KEGG D07775 Yes
ChEBI CHEBI:51066 Yes
ChEMBL CHEMBL1201216 
Chemical data
Formula C19H27N5
Molar mass 325.451 g/mol

//////Дапипразол ,  Dapiprazole, AF-2139, Remydrial, Rev-Eyes, Reversil, Glamidolo

n1nc(n2c1CCCC2)CCN4CCN(c3ccccc3C)CC4


Filed under: Uncategorized Tagged: AF-2139, Dapiprazole, Дапипразол, Glamidolo, Remydrial, Rev-Eyes, Reversil

Results of a Survey on ICH Q3D “Elemental Impurities”

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DRUG REGULATORY AFFAIRS INTERNATIONAL

For most companies manufacturing APIs and pharmaceutical products, the implementation of ICH Q3D has a serious impact – as shown in a survey recently carried out by the ECA. Read more about the issues encountered by many companies regarding the assessment and control of elemental impurities and the kind of support they wish.

SEE

http://www.gmp-compliance.org/enews_05395_Results-of-a-Survey-on-ICH-Q3D-%22Elemental-Impurities%22_15499,15332,S-AYL_n.html

One and a half years after the official entry into force of the ICH Q3D Guideline for “Elemental Impurities” and several supporting documents from the ICH (e.g. “Training Package: Modules 0-7“) a number of questions as regards implementation remain.

In a survey recently performed by the ECA, questions were posed about the issues relating to the fulfilling of the requirements laid down in ICH Q3D. The feedback from almost 80 participants from medium and large pharmaceutical companies and API manufacturers located in Germany and other EU Member States shows remarkable results which harsh…

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EDQM’s new Guideline on Electronic Submissions for CEP Applications

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DRUG REGULATORY AFFAIRS INTERNATIONAL

EDQM’s new Guideline on Electronic Submissions for CEP Applications

As of today (June, 1st 2016), the EDQM doesn’t accept any CEP application in paper format. Read more here about the structure of the electronic submission of an application for a Certificate of Suitability and the errors to avoid.

SEE

http://www.gmp-compliance.org/enews_05380_EDQM-s-new-Guideline-on-Electronic-Submissions-for-CEP-Applications_15429,15332,S-WKS_n.html

The EDQM has recently published a document entitled “Guidance for electronic submissions for Certificates of Suitability (CEP) applications” (PA/PH/CEP (09) 108, 3R) in which the authority describes the requirements to be considered for the submission of an application for a CEP. Let us give you the most important message straight away: the EDQM now only accepts CEP applications in the electronic format since June 1st 2016.

Only the following formats are authorised within an application procedure: PDF, NeeS (non-eCTD electronic submission), VNeeS (the respective application format for veterinary purposes) and eCTD. A change of format during an ongoing…

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Ladostigil

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Ladostigil.png

Ladostigil.png

Ladostigil, TV-3,326

(N-propargyl-(3R) aminoindan-5yl)-ethyl methyl carbamate

(3R)-3-(Prop-2-ynylamino)indan-5-yl ethyl(methyl)carbamate; R-CPAI

Carbamic acid, ethylmethyl-, (3R)-2,3-dihydro-3-(2-propynylamino)-1H-inden-5-yl ester

Condition(s): Mild Cognitive Impairment
U.S. FDA Status: Mild Cognitive Impairment (Phase 2)
Company: Avraham Pharmaceuticals Ltd

Target Type: Cholinergic System

CAS No: 209349-27-4
Synonyms: Ladostigil, TV-3326, UNII-SW3H1USR4Q
Molecular Weight: 272.346 g/mol
Chemical Formula: C16-H20-N2-O2
IUPAC Name: (3R)-3-(Prop-2-ynylamino)indan-5-yl ethyl(methyl)carbamate N-Propargyl-(3R)-aminoindan-5-yl) ethyl methyl carbamate

Ladostigil tartrate Structure

CAS 209394-46-7, Ladostigil tartrate

N-Ethyl-N-methylcarbamic acid 3(R)-(2-propynylamino)-2,3-dihydro-1H-inden-5-yl ester L-tartrate

In 2010, ladostigil tartrate was licensed by Technion Research & Development Foundation and Yissum to Avraham for the treatment of Alzheimer’s disease and other neurogenerative diseases.

Ladostigil (TV-3,326) is a novel neuroprotective agent being investigated for the treatment of neurodegenerative disorders likeAlzheimer’s disease, Lewy body disease, and Parkinson’s disease.[1] It acts as a reversible acetylcholinesterase andbutyrylcholinesterase inhibitor, and an irreversible monoamine oxidase B inhibitor, and combines the mechanisms of action of older drugs like rivastigmine and rasagiline into a single molecule.[2][3] In addition to its neuroprotective properties, ladostigil enhances the expression of neurotrophic factors like GDNF and BDNF, and may be capable of reversing some of the damage seen in neurodegenerative diseases via the induction of neurogenesis.[4] Ladostigil also has antidepressant effects, and may be useful for treating comorbid depression and anxiety often seen in such diseases as well.[5][6]

Ladostigil [(N-propargyl-(3R) aminoindan-5yl)-ethyl methyl carbamate] is a dual acetylcholine-butyrylcholineesterase and brain selective monoamine oxidase (MAO)-A and -B inhibitor in vivo (with little or no MAO inhibitory effect in the liver and small intestine), intended for the treatment of dementia co-morbid with extrapyramidal disorders and depression (presently in a Phase IIb clinical study). This suggests that the drug should not cause a significant potentiation of the cardiovascular response to tyramine, thereby making it a potentially safer antidepressant than other irreversible MAO-A inhibitors. Ladostigil was shown to antagonize scopolamine-induced impairment in spatial memory, indicating that it can cause significant increases in rat brain cholinergic activity. Furthermore, ladostigil prevented gliosis and oxidative-nitrative stress and reduced the deficits in episodic and spatial memory induced by intracerebroventricular injection of streptozotocin in rats. Ladostigil was demonstrated to possess potent anti-apoptotic and neuroprotective activities in vitro and in various neurodegenerative rat models, (e.g. hippocampal damage induced by global ischemia in gerbils and cerebral oedema induced in mice by closed head injury). These neuroprotective activities involve regulation of amyloid precursor protein processing; activation of protein kinase C and mitogen-activated protein kinase signaling pathways; inhibition of neuronal death markers; prevention of the fall in mitochondrial membrane potential and upregulation of neurotrophic factors and antioxidative activity. Recent findings demonstrated that the major metabolite of ladostigil, hydroxy-1-(R)-aminoindan has also a neuroprotective activity and thus, may contribute to the overt activity of its parent compound. This review will discuss the scientific evidence for the therapeutic potential use of ladostigil in Alzheimer’s and Lewy Body diseases and the molecular signaling pathways that are considered to be involved in the biological activities of the drug

PAPER

Tetrahedron: Asymmetry (2012), 23(5), 333-338

http://www.sciencedirect.com/science/article/pii/S0957416612001334

Image for unlabelled figure

Graphical absImg(R)-3-(Prop-2-ynylamino)-2,3-dihydro-1H-inden-5-yl ethyl(methyl)carbamate

C16H20N2O2

ee: 89%

View the MathML source (c 1.46, CHCl3)

Source of chirality: the precursor

Absolute configuration: (R)

Contact Us

Yona Geffen CEO
Avraham Pharmaceuticals Ltd.
42 Hayarkon st.
Northern Industrial Zone
Yavneh, 81227
Israel

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US5703059 * Jan 19, 1994 Dec 30, 1997 British Biotech Pharmaceuticals Ltd. Disaccharide ligands for selectins
US5936000 * Jan 16, 1996 Aug 10, 1999 Pharmacia & Upjohn Company 2-aminoindans as selective dopamine D3 ligands
US6271261 * Jun 24, 1997 Aug 7, 2001 Smithkline Beecham Corporation IL-8 receptor antagonists
US6271263 * Mar 2, 1999 Aug 7, 2001 Teva Pharmaceutical Industries, Ltd. Compositions containing and methods of using 1-aminoindan and derivatives thereof and process for preparing optically active 1-aminoindan derivatives
US6303650 * Jun 18, 1999 Oct 16, 2001 Yissum Research Development Company Of The Hebrew University Of Jerusalem Aminoindan derivatives
US6462222 * Aug 31, 2001 Oct 8, 2002 Yissum Research Development Company Of The Hebrew University Of Jerusalem Aminoindan derivatives
US6538025 * Aug 31, 2001 Mar 25, 2003 Teva Pharmaceutical Industries, Ltd. Aminoindan derivatives
US6737547 * Sep 15, 1999 May 18, 2004 Teva Pharmaceutical Industries, Ltd. Compositions containing and methods of using N-acyl-1H-aminoindenes
US20040010038 * Feb 27, 2003 Jan 15, 2004 Eran Blaugrund Propargylamino indan derivatives and propargylamino tetralin derivatives as brain-selective MAO inhibitors
Citing Patent Filing date Publication date Applicant Title
US7649115 Jun 1, 2006 Jan 19, 2010 Jenrin Discovery, Inc. MAO-B inhibitors useful for treating obesity
US8541475 Dec 31, 2009 Sep 24, 2013 Jenrin Discovery, Inc. MAO-B inhibitors useful for treating obesity
US8569545 Jun 2, 2009 Oct 29, 2013 Generics (Uk) Limited Process for the preparation of enantiomerically pure amines
US8809589 Jul 18, 2013 Aug 19, 2014 Generics [Uk] Limited Process for the preparation of enantiomerically pure amines
US20070088004 * Jun 1, 2006 Apr 19, 2007 Mcelroy John F MAO-B inhibitors useful for treating obesity
US20100168068 * Dec 31, 2009 Jul 1, 2010 Jenrin Discovery Mao-b inhibitors useful for treating obesity
US20110184071 * Jun 2, 2009 Jul 28, 2011 Vinayak Gore process for the preparation of amines
US20110218360 * Sep 8, 2011 Dr. Reddy’s Laboratories Ltd. Preparation of rasagiline and salts thereof
CN103443111A * Apr 2, 2012 Dec 11, 2013 高砂香料工业株式会社 Novel ruthenium complex and process for producing optically active alcohol compound using same as catalyst
CN103443111B * Apr 2, 2012 Mar 2, 2016 高砂香料工业株式会社 钌配合物以及以该配合物作为催化剂的光学活性醇化合物的制备方法
WO2013118126A1 Feb 11, 2013 Aug 15, 2013 Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. Ladostigil therapy for immunomodulation
Ladostigil
Ladostigil.png
Systematic (IUPAC) name
[(3R)-3-(prop-2-ynylamino)indan-5-yl]-N-propylcarbamate
Clinical data
Routes of
administration
Oral
Legal status
Legal status
  • Uncontrolled
Identifiers
CAS Number 209349-27-4
ATC code none
PubChem CID 208907
ChemSpider 181005
UNII SW3H1USR4Q Yes
Synonyms [N-propargyl-(3R)-aminoindan-5yl]-N-propylcarbamate
Chemical data
Formula C16H20N2O2
Molar mass 272.34 g/mol

///////////Ladostigil, TV-3,326

c1c(cc2c(c1)CC[C@H]2NCC#C)OC(=O)N(CC)C


Filed under: Uncategorized Tagged: 326, Ladostigil, TV-3

Obeticholic acid

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Obeticholic acid.svg

Obeticholic acid

Obeticholic acid; 6-ECDCA; INT-747; 459789-99-2; 6-Ethylchenodeoxycholic acid; 6alpha-Ethyl-chenodeoxycholic acid;

(4R)-4-[(3R,5S,6R,7R,8S,9S,10S,13R,14S,17R)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoic acid

Molecular Formula: C26H44O4
Molecular Weight: 420.62516 g/mol

NDA Filed

A farnesoid X receptor (FXR) agonist potentially for treatment of primary biliary cirrhosis and nonalcoholic steatohepatitis.

6-ECDCA; DSP-1747; INT-747

CAS No.459789-99-2

Obeticholic acid.png

Obeticholic acid (abbreviated to OCA), is a semi-synthetic bile acid analogue which has the chemical structure 6α-ethyl-chenodeoxycholic acid. It has also been known as INT-747. It is undergoing development as a pharmaceutical agent for severalliver diseases and related disorders. Intercept Pharmaceuticals Inc. (NASDAQ symbol ICPT) hold the worldwide rights to develop OCA outside Japan and China, where it is licensed to Dainippon Sumitomo Pharma.[2]

REVIEW
INT-747(Obeticholic acid; 6-ECDCA) is a potent and selective FXR agonist(EC50=99 nM) endowed with anticholestatic activity. IC50 value: 99 nM(EC50) [1] Target: FXR agonist in vitro: The exposure of rat hepatocytes to 1 microM 6-ECDCA caused a 3- to 5-fold induction of small heterodimer partner (Shp) and bile salt export pump (bsep) mRNA and 70 to 80% reduction of cholesterol 7alpha-hydroxylase (cyp7a1), oxysterol 12beta-hydroxylase (cyp8b1), and Na(+)/taurocholate cotransporting peptide (ntcp) [2]. in vivo: In vivo administration of 6-ECDCA protects against cholestasis induced by E(2)17alpha [2]. high salt (HS) diet significantly increased systemic blood pressure. In addition, HS diet downregulated tissue DDAH expression while INT-747 protected the loss in DDAH expression and enhanced insulin sensitivity compared to vehicle controls [3]. Rats were gavaged with INT-747 or vehicle during 10 days after bile-duct ligation and then were assessed for changes in gut permeability, BTL, and tight-junction protein expression, immune cell recruitment, and cytokine expression in ileum, mesenteric lymph nodes, and spleen. After INT-747 treatment, natural killer cells and interferon-gamma expression markedly decreased, in association with normalized permeability selectively in ileum (up-regulated claudin-1 and occludin) and a significant reduction in BTL [4].

REFERENCES

[1] Verbeke L, et al. The FXR Agonist Obeticholic Acid Prevents Gut Barrier Dysfunction and Bacterial Translocation in Cholestatic Rats. Am J Pathol. 2015 Feb;185(2):409-19.
[2] Ghebremariam YT, et al. FXR agonist INT-747 upregulates DDAH expression and enhances insulin sensitivity in high-salt fed Dahl rats. PLoS One. 2013 Apr 4;8(4):e60653.
[3] Fiorucci S, et al. Protective effects of 6-ethyl chenodeoxycholic acid, a farnesoid X receptor ligand, in estrogen-induced cholestasis. J Pharmacol Exp Ther. 2005 May;313(2):604-12.
[4] Pellicciari R, et al. 6alpha-ethyl-chenodeoxycholic acid (6-ECDCA), a potent and selective FXR agonist endowed with anticholestatic activity. J Med Chem. 2002 Aug 15;45(17):3569-72.

Invention and development

The natural bile acid, chenodeoxycholic acid, was identified in 1999 as the most active physiological ligand for the farnesoid X receptor (FXR), which is involved in many physiological and pathological processes. A series of alkylated bile acid analogues were designed, studied and patented by Roberto Pellicciari and colleagues at the University of Perugia, with 6α-ethyl-chenodeoxycholic acid emerging as the most highly potent FXR agonist.[3] FXR-dependent processes in liver and intestine were proposed as therapeutic targets in human diseases.[4] Obeticholic acid is the first FXR agonist to be used in human drug studies.

Clinical studies

OCA is undergoing development in phase 2 and 3 studies for specific liver and gastrointestinal disorders.[5]

Primary biliary cirrhosis

Primary biliary cirrhosis (PBC) is an auto-immune, inflammatory liver disease which produces bile duct injury, fibrosis, cholestasisand eventual cirrhosis. It is much more common in women than men and can cause jaundice, itching (pruritus) and fatigue.Ursodeoxycholic acid therapy is beneficial, but the disease often progresses and may require liver transplantation.[6] Animal studies suggested that treatment with FXR agonists should be beneficial in cholestatic diseases such as PBC.[7] OCA at doses between 10 mg and 50 mg was shown to provide significant biochemical benefit, but pruritus was more frequent with higher doses.[8][9] The results of a randomized, double-blind phase 3 study of OCA, 5 mg or 10 mg, compared to placebo (POISE) were presented in April 2014, and showed that the drug met the trial’s primary endpoint of a significant reduction in serum alkaline phosphatase, abiomarker predictive of disease progression, liver transplantation or death.[10]

Nonalcoholic steatohepatitis (NASH)

Non-alcoholic steatohepatitis is a common cause of abnormal liver function with histological features of fatty liver, inflammation andfibrosis. It may progress to cirrhosis and is becoming an increasing indication for liver transplantation. It is increasing in prevalence. OCA is proposed to treat NASH.[11] A phase 2 trial published in 2013 showed that administration of OCA at 25 mg or 50 mg daily for 6 weeks reduced markers of liver inflammation and fibrosis and increased insulin sensitivity.[12]

The Farnesoid X Receptor Ligand Obeticholic Acid in Nonalcoholic Steatohepatitis Treatment (FLINT) trial, sponsored by NIDDK, was halted early in January 2014, after about half of the 283 subjects had completed the study, when a planned interim analysis showed that a) the primary endpoint had been met and b) lipid abnormalities were detected and arose safety concerns. Treatment with OCA (25 mg/day for 72 weeks) resulted in a highly statistically significant improvement in the primary histological endpoint, defined as a decrease in the NAFLD Activity Score of at least two points, with no worsening of fibrosis. 45% (50 of 110) of the treated group had this improvement compared with 21% (23 of 109) of the placebo-treated controls.[13] However concerns about longterm safety issues such as increased cholesterol and adverse cardiovascular events may warrant the concomitant use of statins in OCA-treated patients.[14]

Portal hypertension

Animal studies suggest that OCA improves intrahepatic vascular resistance and so may be of therapeutic benefit in portal hypertension.[15] An open label phase 2a clinical study is under way.

Bile acid diarrhea

Bile acid diarrhea (also called bile acid malabsorption) can be secondary to Crohn’s disease or be a primary condition. Reduced median levels of FGF19, an ileal hormone that regulates increased hepatic bile acid synthesis, have been found in this condition.[16] FGF19 is potently stimulated by bile acids and especially by OCA.[17] A proof of concept study of OCA (25 mg/d) has shown clinical and biochemical benefit.[18]

SYNTHESIS

CN 105541953

Take 10g of austempered cholic acid 89.6% purity crude (single hetero greater than 2%), 3 times its weight of acetone and added to their 20% by weight of triethylamine was added, was heated at reflux for 2h, cooled slowly to 10 ° C, the precipitated crystals were filtered to give Obey acid organic amine salt crystals.

Acidification [0020] The organic amine salts Obey acid crystals were dissolved with purified water after 10wt% by mass percentage to the PH value of 2.0 with dilute hydrochloric acid, filtered and dried to give purified Obey acid.

[0021] The purified Obey acid ethyl acetate dissolved by heating and then cooling to 20 ° C, the precipitated crystals were filtered and dried to obtain a purity of 98.7% recrystallization Obey acid (single hetero less than 0.1%), recovery was 84.5%.

PATENT

 WO 2016045480 

Obey acid (as shown in formula I) is a semi-synthetic chenodeoxycholic acid derivative, for the treatment of high blood pressure, the portal vein and liver diseases, including primary biliary cirrhosis, bile acid diarrhea, non-alcoholic steatohepatitis. Obey acid through activation of FXR receptors play a role, FXR is a nuclear receptor, is expressed mainly in the liver, intestine, kidney, and it can be adjusted with acids fat and carbohydrate metabolism related gene expression in bile, also regulate immune response. FXR activation can inhibit the synthesis of bile acids, bile acids prevent excessive accumulation of toxic reactions caused.

 

 

WO2002072598 debuted Obey acid preparation method (shown below), which in strong alkaline conditions to give compound VII by alkylation with ethyl iodide compound VI directly, through reducing compound VII prepared and carboxy deprotection Obey acid. However, due to direct alkylation with ethyl iodide poor selectivity and yield is too low, the synthesis process is difficult to achieve amplification synthesis.

 

Obey bile acid synthesis (WO2002072598)

 

WO2006122977 above synthesis process has been improved (see below), the process by the silicon compound IX into protected enol compound X, compound X and acetaldehyde after dehydration condensation to give compound Vb, after compound Vb in alkaline conditions under palladium on carbon hydrogenation to give compound XI, after a carbonyl compound XI reduction system Obey acid.

 

 

Obey bile acid synthesis (WO2006122977)

 

The synthetic process can be achieved, although the enlarged combined, however, the compound Vb produce large amounts of byproducts under strongly alkaline conditions palladium on carbon hydrogenation process for preparing high temperature and strong alkaline compound XI during this step leading to the separation of income a lower rate (about 60%), low yield of this step may be due to compound Vb and XI in unprotected hydroxy dehydration occurs under strongly basic (30% NaOH) and high temperature (95-105 ℃) conditions side effects caused.
synthesis of bile acids Obey,

Obey bile acid synthesis route is as follows:

PATENT

CN 105175473

According to Obey acid 6 was prepared in the form of C Patent Document W02013192097A1 reaction of Example 1, as follows:

The 3 a – hydroxy -6 a – ethyl-7-keto -5 P – 24-oic acid (. 86g, 205 4mmol), water (688mL) and 50% (w / w) hydrogen sodium hydroxide solution (56. 4mL) and the mixture of sodium borohydride (7. 77g, 205. 4mmol) in a mixture of 50% (w / w) sodium hydroxide solution (1.5 mL of) and water (20 mL) in 90 ° in C to 105 ° C reaction. Was heated with stirring under reflux for at least 3 hours, the reaction was completed, the reaction solution was cooled to 80 ° C. Between 30 ° C at 50 ° C of citric acid (320. 2g, anhydrous), a mixture of n-butyl acetate (860 mL of) and water (491mL) to ensure an acidic pH of the aqueous phase was separated. Evaporation of the organic phase was distilled to give the residue was diluted with n-butyl acetate, slowly cooled to 15 ° C to 20 ° C, centrifugation. The crude product was crystallized from n-butyl acetate. After Obey acid isolated by n-butyl acetate (43mL, 4 times), dried samples were dried at 80 ° C under vacuum. To give 67. 34g (77. 9%) crystalline form C Obey acid.

References

  1.  Gioiello, Antimo; Macchiarulo, Antonio; Carotti, Andrea; Filipponi, Paolo; Costantino, Gabriele; Rizzo, Giovanni; Adorini, Luciano; Pellicciari, Roberto (April 2011). “Extending SAR of bile acids as FXR ligands: Discovery of 23-N-(carbocinnamyloxy)-3α,7α-dihydroxy-6α-ethyl-24-nor-5β-cholan-23-amine”. Bioorganic & Medicinal Chemistry 19 (8): 2650–2658.doi:10.1016/j.bmc.2011.03.004.
  2.  Wall Street Journal. “A $4 Billion Surprise for 45-Person Biotech”. Retrieved10 January 2014.
  3.  Pellicciari R, Fiorucci S, Camaioni E, Clerici C, Costantino G, Maloney PR, Morelli A, Parks DJ, Willson TM (August 2002). “6alpha-ethyl-chenodeoxycholic acid (6-ECDCA), a potent and selective FXR agonist endowed with anticholestatic activity”. J. Med. Chem. 45(17): 3569–72. doi:10.1021/jm025529g. PMID 12166927.
  4.  Rizzo G, Renga B, Mencarelli A, Pellicciari R, Fiorucci S (September 2005). “Role of FXR in regulating bile acid homeostasis and relevance for human diseases”. Curr. Drug Targets Immune Endocr. Metabol. Disord. 5 (3): 289–303. doi:10.2174/1568008054863781.PMID 16178789.
  5.  “ClinicalTrials.gov”.
  6.  Hirschfield GM, Gershwin ME (January 2013). “The immunobiology and pathophysiology of primary biliary cirrhosis”. Annu Rev Pathol 8: 303–30. doi:10.1146/annurev-pathol-020712-164014. PMID 23347352.
  7. Jump up^ Lindor, KD (May 2011). “Farnesoid X receptor agonists for primary biliary cirrhosis”.Current opinion in gastroenterology 27 (3): 285–8.doi:10.1097/MOG.0b013e32834452c8. PMID 21297469.
  8. Jump up^ Fiorucci S, Cipriani S, Mencarelli A, Baldelli F, Bifulco G, Zampella A (August 2011). “Farnesoid X receptor agonist for the treatment of liver and metabolic disorders: focus on 6-ethyl-CDCA”. Mini Rev Med Chem 11 (9): 753–62. doi:10.2174/138955711796355258.PMID 21707532.
  9. Jump up^ Hirschfield GM, Mason A, Luketic V, Lindor K, Gordon SC, Mayo M, Kowdley KV, Vincent C, Bodhenheimer HC, Parés A, Trauner M, Marschall HU, Adorini L, Sciacca C, Beecher-Jones T, Castelloe E, Böhm O, Shapiro D (2015). “Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid”.Gastroenterology 148 (4): 751–61.e8. doi:10.1053/j.gastro.2014.12.005.PMID 25500425.
  10. Jump up^ Intercept Pharma. “Press release: Intercept Announces Positive Pivotal Phase 3 POISE Trial Results”. Retrieved March 27, 2014.
  11. Jump up^ Adorini L, Pruzanski M, Shapiro D (September 2012). “Farnesoid X receptor targeting to treat nonalcoholic steatohepatitis”. Drug Discov. Today 17 (17–18): 988–97.doi:10.1016/j.drudis.2012.05.012. PMID 22652341.
  12. Jump up^ Mudaliar S, Henry RR, Sanyal AJ, Morrow L, Marschall HU, Kipnes M, Adorini L, Sciacca CI, Clopton P, Castelloe E, Dillon P, Pruzanski M, Shapiro D (September 2013). “Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease”. Gastroenterology 145 (3): 574–82.e1.doi:10.1053/j.gastro.2013.05.042. PMID 23727264.
  13. Jump up^ Neuschwander-Tetri BA, Loomba R, Sanyal AJ, Lavine JE, Van Natta ML, Abdelmalek MF, Chalasani N, Dasarathy S, Diehl AM, Hameed B, Kowdley KV, McCullough A, Terrault N, Clark JM, Tonascia J, Brunt EM, Kleiner DE, Doo E (2015). “Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial”. Lancet 385 (9972): 956–65.doi:10.1016/S0140-6736(14)61933-4. PMID 25468160.
  14. Jump up^ http://www.thestreet.com/story/12714549/1/intercept-pharma-government-scientists-spar-over-negative-safety-of-liver-drug-emails-show.html?puc=yahoo&cm_ven=YAHOO
  15.  Verbeke L, Farre R, Trebicka J, Komuta M, Roskams T, Klein S, Vander Elst I, Windmolders P, Vanuytsel T, Nevens F, Laleman W (November 2013). “Obeticholic acid, a farnesoid-X receptor agonist, improves portal hypertension by two distinct pathways in cirrhotic rats”. Hepatology 59 (6): :2286–98. doi:10.1002/hep.26939. PMID 24259407.
  16.  Walters JR, Tasleem AM, Omer OS, Brydon WG, Dew T, le Roux CW (November 2009). “A new mechanism for bile acid diarrhea: defective feedback inhibition of bile acid biosynthesis”. Clin. Gastroenterol. Hepatol. 7 (11): 1189–94.doi:10.1016/j.cgh.2009.04.024. PMID 19426836.
  17.  Zhang JH, Nolan JD, Kennie SL, Johnston IM, Dew T, Dixon PH, Williamson C, Walters JR (May 2013). “Potent stimulation of fibroblast growth factor 19 expression in the human ileum by bile acids”. Am. J. Physiol. Gastrointest. Liver Physiol. 304 (10): G940–8.doi:10.1152/ajpgi.00398.2012. PMC 3652069. PMID 23518683.
  18.  Walters JR, Johnston IM, Nolan JD, Vassie C, Pruzanski ME, Shapiro DA (January 2015). “The response of patients with bile acid diarrhoea to the farnesoid X receptor agonist obeticholic acid”. Aliment. Pharmacol. Ther. 41 (1): 54–64.doi:10.1111/apt.12999. PMID 25329562.

External links

Patent ID Date Patent Title
US8546365 2013-10-01 Bile acid derivatives as FXR ligands for the prevention or treatment of FXR-mediated diseases or conditions
US8377916 2013-02-19 Steroids as agonists for FXR
US8058267 2011-11-15 STEROIDS AS AGONISTS FOR FXR
US7994352 2011-08-09 Process for Preparing 3a(Beta)-7a(Beta)-Dihydroxy-6a(Beta)-Alkyl-5Beta-Cholanic Acid
US7932244 2011-04-26 Bile acid derivatives as FXR ligands for the prevention or treatment of FXR-mediated diseases or conditions
US7786102 2010-08-31 Steroids as agonists for FXR
US2009062526 2009-03-05 NOVEL METHOD OF SYNTHESIZING ALKYLATED BILE ACID DERIVATIVES
US7138390 2006-11-21 Steroids as agonists for fxr
US2005107475 2005-05-19 Methods of using farnesoid x receptor (frx) agonists
Patent ID Date Patent Title
US2016074419 2016-03-17 Preparation and Uses of Obeticholic Acid
US2015359805 2015-12-17 Bile Acid Derivatives as FXR Ligands for the Prevention or Treatment of FXR-Mediated Diseases or Conditions
US2015166598 2015-06-18 Steroids as Agonists for FXR
US2014371190 2014-12-18 Farnesoid X receptor modulators
US2014186438 2014-07-03 COMPOSITIONS COMPRISING EPA AND OBETICHOLIC ACID AND METHODS OF USE THEREOF
US2014148428 2014-05-29 Treatment of Pulmonary Disease
US2014057886 2014-02-27 Bile Acid Derivatives as FXR Ligands for the Prevention or Treatment of FXR-Mediated Diseases or Conditions
US2014024631 2014-01-23 Steroids as Agonists for FXR
US2013345188 2013-12-26 Preparation and Uses of Obeticholic Acid
US8546365 2013-10-01 Bile acid derivatives as FXR ligands for the prevention or treatment of FXR-mediated diseases or conditions
Obeticholic acid
Obeticholic acid.svg
Systematic (IUPAC) name

(3α,5β,6α,7α)-6-Ethyl-3,7-dihydroxycholan-24-oic acidOR

(4R)-4-[(3R,5S,6R,7R,8S,9S,10S,13R,14S,17R)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoic acid

Clinical data
Routes of
administration
Oral
Legal status
Legal status
  • Investigational New Drug
Identifiers
CAS Number 459789-99-2
ATC code A05AA04 (WHO)
PubChem CID 447715
IUPHAR/BPS 3435
ChemSpider 394730
UNII 0462Z4S4OZ
KEGG C15636
ChEMBL CHEMBL566315
Synonyms 6α-ethyl-chenodeoxycholic acid; INT-747
Chemical data
Formula C26H44O4
Molar mass 420.62516 g/mol

/////////6-ECDCA,  DSP-1747,  INT-747, 459789-99-2, Obeticholic acid

CC[C@@H]1[C@@H]2C[C@@H](CC[C@@]2([C@H]3CC[C@]4([C@H]([C@@H]3[C@@H]1O)CC[C@@H]4[C@H](C)CCC(=O)O)C)C)O

CCC1C2CC(CCC2(C3CCC4(C(C3C1O)CCC4C(C)CCC(=O)O)C)C)O


Filed under: Uncategorized Tagged: 459789-99-2, 6-ECDCA, DSP-1747, INT-747, Obeticholic acid

AM 2394

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str1

AM 2394

1-(6′-(2-hydroxy-2-methylpropoxy)-4-((5-methylpyridin-3-yl)oxy)-[3,3′-bipyridin]-6-yl)-3-methylurea

Urea, N-[6′-(2-hydroxy-2-methylpropoxy)-4-[(5-methyl-3-pyridinyl)oxy][3,3′-bipyridin]-6-yl]-N‘-methyl-

CAS 1442684-77-6
Chemical Formula: C22H25N5O4
Exact Mass: 423.1907

Array Biopharma Inc., Amgen Inc. INNOVATORS

AM-2394 is a potent and selective Glucokinase agonist (GKA), which catalyzes the phosphorylation of glucose to glucose-6-phosphate. AM-2394 activates GK with an EC50 of 60 nM, increases the affinity of GK for glucose by approximately 10-fold, exhibits moderate clearance and good oral bioavailability in multiple animal models, and lowers glucose excursion following an oral glucose tolerance test in an ob/ob mouse model of diabetes

Type 2 diabetes mellitus (T2DM) is a disease characterized by elevated plasma glucose in the presence of insulin resistance and inadequate insulin secretion. Glucokinase (GK), a member of the hexokinase enzyme family, catalyzes the phosphorylation of glucose to glucose-6-phosphate in the presence of ATP.

img

str1

Glucokioase i exok ase IV or D> is a glycolytic enssyiris that plays, an importaat. role irt blood sugar regulation .related to glucose utifeattoti a»d metabolism in the liver and pancreatic beta cells. Serving as a glucose sessor, gtoeokiuase controls lasma glucose, levels. Glucokinaae plays a doal rob in .reducing plasma glucose levels; glucose-mediated activation of the en¾ymc in hepatocytes facilitates hepatic giocose npiafcc aad glycogen synthesis, while that la pancreatic beta ceils ultimately induces ins lin seeretio«. Both of these effects in turn reduce plasma glucose levels.

Clinical evidence has shown that, glueokitiase variants with, decreased, and increased activities are associated with mature easel, diabetes of the y ung { O0Y2) and persistent: hyperinsul nemic hypoglycemia &( infancy (PHHI), respectively. lso, aoo n.sulin dependent diabetes rneilitos (NIDDM) patients have been reported to have inappropriately lo giueokaiase activity; Ftirtherrnare. overexpressioa of glucokiuase it* dietary or gesetie animal models of diabetes either prevents, aoKiiorafes, or reverses the progress of pathological. symptoms in the disease. For these reasons, compounds that activate gfecokiaase have been sought by the pitasaaceatjeai liidustry.

International patent application, Publication No. WO 2 7/OS3345, which was published on May 10, 200?, discloses as giocokinase act ators certain 2-an«.aopyridiiie derivatives bearing at the 3 -position a meihyieneoxy-dkrked aromatic group a d on. the ammo group a heteroaryl ring, such as dna/oly! or i A4-lmadiazoiyl

it has .now been found that pyridyl ureas are useful as glneokirtase activators. Cettain of these •compounds have been, found to have an outstanding combination of properties that especially adapts them, for oral use to control plasma glucose levels.

 

 

Novel Series of Potent Glucokinase Activators Leading to the Discovery of AM-2394

Departments of Therapeutic Discovery, Metabolic Disorders, and Pharmacokinetics and Drug Metabolism, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, California 94080, United States
Departments of Metabolic Disorders, Comparative Biology and Safety Sciences and Pharmacokinetics and Drug Metabolism, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States
§ Array BioPharma Inc., 3200 Walnut Street, Boulder, Colorado 80301, United States
ACS Med. Chem. Lett., Article ASAP
DOI: 10.1021/acsmedchemlett.6b00140

http://pubs.acs.org/doi/abs/10.1021/acsmedchemlett.6b00140

 

Abstract Image

Glucokinase (GK) catalyzes the phosphorylation of glucose to glucose-6-phosphate. We present the structure–activity relationships leading to the discovery of AM-2394, a structurally distinct GKA. AM-2394 activates GK with an EC50 of 60 nM, increases the affinity of GK for glucose by approximately 10-fold, exhibits moderate clearance and good oral bioavailability in multiple animal models, and lowers glucose excursion following an oral glucose tolerance test in an ob/ob mouse model of diabetes.

PATENT

WO 2013086397

 http://www.google.com/patents/WO2013086397A1?cl=en

 COPYING ERROR

Example. 1734 t¾^Jtiyi¾rea

Figure imgf000643_0007

Step A: In 100 mL of DMA were corafeiaed 1 ^545miSO- -ll«omp ridinr2-yl)-3-i«e hir8a- (17.5 g, 70,5 ii!-!to!). 5-o:ieS:t}yI yiidlii~3- ). (9,24 g, S4.7 ΪΗΪΪΪΟ!}, sad CO · (10.1 g, 77.6 mmo!) mid heated to 90 *C for 5 days. After that time, the reaction was om lete a d to it was added water arid DCM and stirred vigorously for 3 hr. The resulting solid was isolated via vacuum .filtratiott nd the cake was wasted mill rater and DCM. The DCM in tli aqueous rime was dried vdth a stream of aidogeji aad vigorous sbrriug. Use resulting solid was then collected via vacuum filtration aad these solids were

Stirred vig rousl in f 0% MeOH irt EtOAc arid die res dtipg solid was colleeied. via vactiiars fiirfati m.

Trie two batches wen i coiiibiaed to yield I-(5-bmmo-4 5^»ie†fey pyiidin-3-yl xy)p Tidin-2- d 3~ metbySurea (I S J g, 5 3.7 om»)i, 76% yield).

S e .8: In 2 niL ofc ioxane

Figure imgf000644_0001

yI) iyridMJ-2-yios:y)pf¾ps3i-2-oI (0,098 g, 0.33 «ΜΠΟΪ), -i5-bs¾tao-4-{5-a3fidiy I py f idia-3 – ylosy)f5yridia-2-yl)-3-raethyl«rea (0.075 g, 0.22 tn ol.. t, and.2M poiass.ua» carbonate (0.33 ml, 0.67 m oi} artd tfets was s parged wi h At .for 10 mia before PdC§4dppl)*DCM (0.01 g g, 0.022 msttol) was added and dre reae!io a was sparged for aaotber 5 ma-, ir efore a was sealed and heated to 100 oversight The react! art was then loaded directly onto s ilica gel (50% acetone to PCM w4i. }%

MH40H) to afford i – (6′-(2diydioxy-2i-H5eth:ylpropCis:y) -4-{ 5″i:t re th y Ipy r i d i rt -3- io s y ) -3 ,3 : -bipyr id i rt -6- yl)-3-aie5¾ylt)rea φ.? 42 , 0.096 m ol, 43 % yield). !1 1 HMR (400 Mife, CDCij) 3 ppm 9.06 is,. !H),

S.33 is, 1H>, 8,27 (rs 2H), 8. Π (s, I H): K. (s, IHU 82 (dd, j-S.fi, 5.9 H HI), 1.21 (S !H), 6,«8

(d, Hz, i i i ). 6. ,4 (s:. m>, 4.25 (s, 2H), 2,87 (dj =4,3 Hz„ 3H) 2,37 (s, 3H>. 1 .33 is, <SH). Mass speetram (apci) tar/, : – 423.9 (M÷H).

REFERENCES

Novel Series of Potent Glucokinase Activators Leading to the Discovery of AM-2394
Paul J. Dransfield, Vatee Pattaropong, Sujen Lai, Zice Fu, Todd J. Kohn, Xiaohui Du, Alan Cheng, Yumei Xiong, Renee Komorowski, Lixia Jin, Marion Conn, Eric Tien, Walter E. DeWolf Jr., Ronald J. Hinklin, Thomas D. Aicher, Christopher F. Kraser, Steven A. Boyd, Walter C. Voegtli, Kevin R. Condroski, Murielle Veniant-Ellison, Julio C. Medina, Jonathan Houze, and Peter Coward
Publication Date (Web): May 23, 2016 (Letter)
DOI: 10.1021/acsmedchemlett.6b00140

/////////Glucokinase activator,  GKA,  AM-2394, 1442684-77-6, AM 2394, Amgen

O=C(NC)NC1=CC(OC2=CC(C)=CN=C2)=C(C3=CC=C(OCC(C)(O)C)N=C3)C=N1


Filed under: Uncategorized Tagged: 1442684-77-6, AM-2394, amgen, GKA, Glucokinase Activator

3,5-Dibromo-N-(4,6-difluorobenzo[d]thiazol-2-yl)thiophene-2-carboxamide having potent anti-norovirus activity

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STR1

3,5-Dibromo-N-(4,6-difluorobenzo[d]thiazol-2-yl)thiophene-2-carboxamide

New and novel anti-norovirus agents

There is an urgent need for structurally novel anti-norovirus agents. In this study, we describe the synthesis, anti-norovirus activity, and structure–activity relationship (SAR) of a series of heterocyclic carboxamide derivatives. Heterocyclic carboxamide 1 (50% effective concentration (EC50)=37  µM) was identified by our screening campaign using the cytopathic effect reduction assay. Initial SAR studies suggested the importance of halogen substituents on the heterocyclic scaffold and identified 3,5-di-boromo-thiophene derivative 2j (EC50=24 µM) and 4,6-di-fluoro-benzothiazole derivative 3j (EC50=5.6 µM) as more potent inhibitors than 1. Moreover, their hybrid compound, 3,5-di-bromo-thiophen-4,6-di-fluoro-benzothiazole 4b, showed the most potent anti-norovirus activity with a EC50 value of 0.53 µM (70-fold more potent than 1). Further investigation suggested that 4b might inhibit intracellular viral replication or the late stage of viral infection.

3,5-Dibromo-N-(4,6-difluorobenzo[d]thiazol-2-yl)thiophene-2-carboxamide (4b)

STR1

According to the same procedure used for 2f, starting from 3,5-dibromothiophene-2-carboxylic acid (286 mg, 1.00 mmol) and 4,6-difluorobenzo[d]thiazol-2-amine (204 mg, 1.10 mmol), 4b (270 mg, 60%) was obtained as white powder. mp: 245–246°C. 1H-NMR (DMSO-d6) δ: 7.43 (1H, dt, J=10.2, 2.0 Hz), 7.56 (1H, s), 7.83 (1H, dd, J=8.4, 2.0 Hz). 13C-NMR (DMSO-d6) δ: 102.2 (dd, J=28.0, 23.1 Hz), 104.7 (dd, J=26.4, 3.3 Hz), 114.3, 118.4, 131.4 (d, J=7.4 Hz), 134.3 (d, J=10.7 Hz), 134.9, 135.2, 152.7 (d, J=241.2, 20.7 Hz), 158.3 (dd, J=242.2, 10.7 Hz), 159.0, 159.7. HPLC purity: >99%, ESI-MS m/z 453 [M+H]+.

Antiviral Activity and Cytotoxicity of Tetra-halogenated Hybrid Compounds

Compound R6 R7 R8 EC50 (µM)a) CC50 (µM)b)
4a Cl H H 2.1 >100
4b Br H Br 0.53 >100
4c Cl H Cl 1.1 >100
4d Cl Cl H 1.4 31

a) EC50 was evaluated by the CPE reduction assay. 280 TCID50/50  µL of MNV and a dilution series of each compound were incubated for 30 min. The mixture was exposed to RAW264.7 cells for 1 h (in duplicate). b) Cytotoxicity was evaluated by the WST-8 assay. RAW264.7 cells were treated with dilution series of each compound (in triplicate) for 72 h.

Discovery and Synthesis of Heterocyclic Carboxamide Derivatives as Potent Anti-norovirus Agents

How to Kill Norovirus

Three Methods:Killing Norovirus with Good HygieneKilling Norovirus in Your HomeTreating NorovirusCommunity Q&A

Norovirus is a contagious virus that affects many people each year. You can get norovirus through interaction with an infected person, by eating contaminated food, touching contaminated surfaces, or drinking contaminated water. However, there are ways to kill norovirus before it infects you. To do this, you will have to maintain personal hygiene and keep your home contamination-free.

Method1

Killing Norovirus with Good Hygiene

  1. Image titled Kill Norovirus Step 1
    1

    Wash your hands thoroughly. If you think you may have come into contact with the virus, you must wash your hands thoroughly to avoid the spread of infection. To wash your hands to avoid contamination, use soap and hot water. Alcohol hand sanitizer is generally considered ineffective against this particular kind of virus. You should wash your hands if[1]:

    • You have come into contact with someone who has norovirus.
    • Before and after you interact with someone with norovirus.
    • If you visit a hospital, even if you don’t think you interacted with anyone with norovirus.
    • After going to the bathroom.
    • Before and after eating.
    • If you are a nurse or doctor, wash your hands before and after coming into contact with an infected patient, even if you wear gloves.
  2. Image titled Kill Norovirus Step 2
    2

    Avoid cooking for others if you are sick. If you have been infected and are sick, do not handle any food or cook for others in your family. If you do, they are almost certain to get the infection too.

    • If a family member is contaminated, do not let them cook for anyone else. Try to limit the amount of time healthy family members spend with the sick family member.
  3. Image titled Kill Norovirus Step 3
    3

    Wash your food before eating or cooking it. Wash all food items such as meats, fruits and vegetables thoroughly before consumption or for use in cooking. This is important as norovirus has the tendency to survive even at temperatures well above 140 degrees Fahrenheit (60 degrees Celsius).[2]

    • Remember to carefully wash any vegetables or fruit, before consuming them, whether you prefer them fresh or cooked.
  4. Image titled Kill Norovirus Step 4
    4

    Cook your food thoroughly before eating it. Seafood should be cooked thoroughly before eating it. Quick steaming your food will generally not kill the virus, as it can survive the steaming process. Instead, bake or boil your food at temperatures higher than 140F (60C) if you are concerned about it’s origins.[3]

    • If you suspect any kind of food of being contaminated, you should dispose of it immediately. For instance, if a contaminated family member handled the food, you should either throw the food out or isolate it and make sure that only the person who already has the virus eats it.

Method2

Killing Norovirus in Your Home

  1. Image titled Kill Norovirus Step 5
    1

    Use bleach to clean surfaces. Chlorine bleach is an effective cleaning agent that kills norovirus. Increase the concentration or buy a new bottle of chlorine bleach if the bleach you have has been open for more than a month. Bleach becomes less effective the longer it remains open. Before applying bleach to a visible surface, test it somewhere that is not easily seen to make sure that it won’t damage the surface. If the surface is damaged by bleach, you can also use phenolic solutions, such as Pine-Sol, to clean the surface. There are certain concentrations of chlorine bleach you can use for different surfaces.[4]

    • For stainless steel surfaces and items used for food consumption: Dissolve one tablespoon of bleach in a gallon of water and clean the stainless steel.
    • For non-porous surfaces like countertops, sinks, or tile floors: Dissolve one third of a cup of bleach in a gallon of water.
    • For porous surfaces, like wooden floors: Dissolve one and two thirds of a cup of bleach in a gallon of water.
  2. Image titled Kill Norovirus Step 6
    2

    Rinse surfaces with clean water after using bleach. After cleaning the surfaces, leave the solution to work for 10 to 20 minutes. After the time period elapses, rinse the surface with clean water. After these two steps, close off the area, and leave it like that for one hour.

    • Leave the windows open, if possible, as breathing in bleach can be hazardous to your health.
  3. Image titled Kill Norovirus Step 7
    3

    Clean areas exposed to feces or vomit. For areas exposed to feces or vomit contamination there are special cleaning procedures that you should try to follow. This is because the vomit or feces of a person contaminated with norovirus can easily cause you to become infected. To clean the vomit or feces:

    • Put disposable gloves on. Consider wearing a facemask that covers your mouth and nose as well.
    • Using paper towels, gently clean the vomit and feces. Be careful not to splash or drip while cleaning.
    • Use disposable cloths to clean and disinfect the entire area with chlorine bleach.
    • Use sealed plastic bags to dispose of all the waste materials.
  4. Image titled Kill Norovirus Step 8
    4

    Clean your carpets. If the feces or vomit gets on a carpeted area, there are other steps you can take to make sure that the area is clean and disinfected. To clean the carpeted area:

    • Wear disposable gloves if you can while cleaning the carpets. You should also consider wearing a facemask that covers your mouth and nose.
    • Use any absorbent material to clean all the visible feces or vomit. Place all contaminated materials in a plastic bag to prevent aerosols from forming. The bag should be sealed and put into the garbage can.
    • The carpet should then be cleaned with steam at 170 degrees Fahrenheit (76 degrees Celsius) for about five minutes, or, if you want to save time, clean the carpet for one minute with 212 degrees Fahrenheit (100 degrees Celsius) steam.
  5. Image titled Kill Norovirus Step 9
    5

    Disinfect clothing. If any of your clothing or a family member’s clothing has become contaminated, or is suspected of having been contaminated, you should take care when washing the fabric. To clean clothing and linens:

    • Remove any traces of vomit or feces by wiping it away with paper towels or a disposable absorbent material.
    • Put the contaminated clothing into the washing machine in a pre-wash cycle. After this stage is complete, wash the clothes using a regular washing cycle and detergent. The clothes should be dried separately from the uncontaminated clothes. A drying temperature exceeding 170 degrees Fahrenheit is recommended.
    • Do not wash contaminated clothing with uncontaminated cleaning.

Method3

Treating Norovirus

  1. Image titled Kill Norovirus Step 10
    1

    Recognize symptoms. If you think you may have been infected with norovirus, it is helpful to know what symptoms to look for. If you do have the virus, the following steps will help you to deal with the illness while it lasts. Symptoms include[5]:

    • Fever. Just like in any other infection, the norovirus infection will cause fever. Fever is a way in which the body fights infection. The body temperature will rise, making the virus more vulnerable to the immune system. Your body temperature will most likely rise above 100.4 degrees Fahrenheit (38 degrees Celsius) when suffering from a Norovirus infection.
    • Headaches. High body temperatures will cause blood vessels to dilate in your entire body, including your head. The high amount of blood inside your head will cause pressure to build up, and the protective membranes covering your brain will suffer inflammation and become painful.
    • Stomach cramps. Norovirus infections usually settle in the stomach. Your stomach may become inflamed, causing pain.
    • Diarrhea. Diarrhea is a common symptom of Norovirus contamination. It occurs as a defense mechanism, through which the body is trying to flush out the virus.
    • Vomiting. Vomiting is another common symptom of an infection with Norovirus. Like in the case of diarrhea, the body is trying to eliminate the virus from the system by vomiting.
  2. Image titled Kill Norovirus Step 11
    2

    Understand that while there is no treatment, there are ways to manage symptoms. Unfortunately, there is no specific drug that acts against the virus. However, you can combat the symptoms that the norovirus causes. Remember that the virus is self-limiting, which means that it generally goes away on its own.

    • The virus generally lasts for a few days to a week.
  3. Image titled Kill Norovirus Step 12
    3

    Drink lots of fluids. Consuming a lot of water and other fluids will help to keep you hydrated. This can help to keep your fever low and your headaches to a minimum. It is also important to drink water if you have been vomiting or have had diarrhea. When these too symptoms occur, it is very likely that you will become dehydrated.

    • If you get bored with water, you can drink ginger tea, which may help to manage your stomach pains while also hydrating you.
  4. Image titled Kill Norovirus Step 13
    4

    Consider taking anti-vomiting drugs. Anti-emetic (vomit-preventing) drugs such as ondansetron and domperidone can be given to provide symptomatic relief if you are vomiting frequently.[6]

    • However, keep in mind that these drugs can only be obtained with a prescription from your doctor.
  5. Image titled Kill Norovirus Step 14
    5
    Seek medical help if the infection is severe. As mentioned above, most infections subside after a few days. If the virus persists for longer than a week, you should consider seeking medical help. This is particularly important if the person who is sick is a child or elderly person, or a person with lowered immunity

Filed under: Uncategorized Tagged: antiviral activity, heterocyclic carboxamide, murine norovirus, norovirus

WHO defines Requirements on Zones E and F

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DRUG REGULATORY AFFAIRS INTERNATIONAL

In May, the WHO published a draft guideline which describes the recommendations for ventilation systems used in the manufacture of non-sterile dosage forms. It also contains for the first time a definition for microbial requirements with regard to the zones E and F. Read more about the ventilation sytems recommendations.

http://www.gmp-compliance.org/enews_05367_WHO-defines-Requirements-on-Zones-E-and-F_15221,15231,15612,15266,Z-PEM_n.html

In May 2016, the WHO published a draft guideline which describes the recommendations for ventilation systems used in the manufacture of non-sterile dosage forms. From a technical point of view, the guideline is very interesting and includes a detail which may be overlooked: it contains – as first international GMP guideline – a proposal for the definition of microbiological requirements concerning the zones E and F. So far, the approach to extend the zoning via the zones A-D defined in Annex 1 to the zones E and F and thus define microbial limits had only been available in an Aide Memoire…

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Filed under: Uncategorized

ND 630, NDI 010976

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str1

ndi molecul
str1
ND 630, NDI 010976,  ND-630, NDI-010976
1,4-dihydro-1-[(2R)-2-(2-methoxyphenyl)-2-[(tetrahydro-2H-pyran-4-yl)oxy]ethyl]-α,α,5-trimethyl-6-(2-oxazolyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-3(2H)-acetic acid
2-[l-[2-(2-methoxyphenyl)-2-(oxan-4-yloxy)ethyl]-5- methyl-6-(l,3-oxazol-2-yl)-2,4-dioxo-lH,2H,3H,4H-thieno[2,3-d]pyrimidin-3-yl]-2- methylpropanoic acid
2-[1-[(2R)-2-(2-methoxyphenyl)-2-(oxan-4-yloxy)ethyl]-5-methyl-6-(1,3-oxazol-2-yl)-2,4-dioxothieno[2,3-d]pyrimidin-3-yl]-2-methylpropanoic acid
CAS 1434635-54-7
Thieno[2,3-d]pyrimidine-3(2H)-acetic acid, 1,4-dihydro-1-[(2R)-2-(2-methoxyphenyl)-2-[(tetrahydro-2H-pyran-4-yl)oxy]ethyl]-α,α,5-trimethyl-6-(2-oxazolyl)-2,4-dioxo-
Molecular Formula: C28H31N3O8S
Molecular Weight: 569.62604 g/mol
Company Nimbus Therapeutics LLC
Description Small molecule allosteric inhibitor of acetyl-coenzyme A carboxylase alpha (ACACA; ACC1) and acetyl-coenzyme A carboxylase beta (ACACB; ACC2)
Molecular Target Acetyl-Coenzyme A carboxylase alpha (ACACA) (ACC1) ; Acetyl-Coenzyme A carboxylase beta (ACACB) (ACC2)
Mechanism of Action Acetyl-coenzyme A carboxylase alpha (ACACA) (ACC1) inhibitor; Acetyl-coenzyme A carboxylase beta (ACACB) (ACC2) inhibitor
Therapeutic Modality Small molecule
Preclinical Diabetes mellitus; Hepatocellular carcinoma; Metabolic syndrome; Non-alcoholic steatohepatitis; Non-small cell lung cancer
CHEMBL3407547.png

Acetyl CoA carboxylase 1/2 allosteric inhibitors – Nimbus Therapeutics

The Liver Meeting 2015 – American Association for the Study of Liver Diseases (AASLD) – 2015 Annual Meeting, San Francisco, CA, USA

Nimbus compounds targeting liver disease in rat models

Data were presented by Geraldine Harriman, from Nimbus Therapeutics, from rat models using acetyl-CoA carboxylase (ACC) inhibitors NDI-010976 (ND-630) and N-654, which improved metabolic syndrome endpoints, decreased liver steatosis, decreased expression of inflammatory markers and improved fibrosis. The hepatotropic ACC inhibitor NDI-010976 had IC50 values of 2 and 7 nM for ACC1 and 2, respectively, EC50 values in HepG2 serum free and 10% serum of 9 and 66 nM, respectively, and 2-fold C2C12 fatty acid oxidation (FAOxn) stimulation at 200 nM. Rat FASyn (synthase), malonyl-CoA (liver) and malonyl-COA (muscle) respective ED50 values were 0.14 mg/kg po, 0.8 and 3 mg/kg. The rat respiratory quotient (RQ) MED was 3 mg/kg po. ADME data showed low multispecies intrinsic clearance (human, mouse, rat, dog, monkey). NDI-010976 was eliminated predominantly as the parent drug. Additionally, P450 inhibition was > 50 microM. In liver and muscle, NDI-010976 modulated key metabolic parameters including a dose-dependent reduction in the formation of the enzymatic product of acetyl coA carboxyloase malonyl coA; the ED50 value was lower in muscle. The drug also decreased FASyn dose dependently and increased fatty acid oxidation in the liver (EC50 = 0.14 mg/kg). In 28-day HS DIO rats, NDI-010976 favorably modulated key plasma and liver lipids, including decreasing liver free fatty acid, plasma triglycerides and plasma cholesterol; this effect was also seen in 37-day ZDF rats

 PATENT

http://www.google.com/patents/WO2013071169A1?cl=en

Example 76: Synthesis of 2-[l-[2-(2-methoxyphenyl)-2-(oxan-4-yloxy)ethyl]-5- methyl-6-(l,3-oxazol-2-yl)-2,4-dioxo-lH,2H,3H,4H-thieno[2,3-d]pyrimidin-3-yl]-2- methylpropanoic acid (1-181).

Synthesis of compound 76.1. Into a 250-mL 3 -necked round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed oxan-4-ol (86 g, 842.05 mmol, 2.01 equiv) and FeCl3 (10 g). This was followed by the addition of 57.2 (63 g, 419.51 mmol, 1.00 equiv) dropwise with stirring at 0 °C. The resulting solution was stirred for 3 h at room temperature. The resulting solution was diluted with 500 mL of H20. The resulting solution was extracted with 3×1000 mL of ethyl acetate and the organic layers combined. The resulting solution was extracted with 3×300 mL of sodium chloride (sat.) and the organic layers combined and dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 : 10). This resulted in 22 g (21%) of 76.1 as a white solid.

Synthesis of compound 76.2. The enantiomers of 76.1 (22g) were resolved by chiral preparative HPLC under the following conditions (Gilson Gx 281): Column: Venusil Chiral OD-

H, 21.1 *25 cm, 5 μιη; mobile phase: hexanes (0.2% TEA) and ethanol (0.2% TEA) (hold at 10% ethanol (0.2%TEA) for 13 min); detector: UV 220/254 nm. 11.4 g (52%) of 76.2 were obtained as a white solid.

Synthesis of compound 76.3. Into a 500-mL 3-necked round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed 70.1 (12 g, 20.49 mmol, 1.00 equiv), tetrahydrofuran (200 mL), 76.2 (6.2 g, 24.57 mmol, 1.20 equiv) and DIAD (6.5 g, 32.18 mmol, 1.57 equiv). This was followed by the addition of a solution of triphenylphosphane (8.4 g, 32.03 mmol, 1.56 equiv) in tetrahydrofuran (100 mL) dropwise with stirring at 0 °C in 60 min. The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 :5). This resulted in 17 g (crude) of 76.3 as a white solid.

Synthesis of compound 76.4. Into a 500-mL 3-necked round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed 76.3 (17 g, crude), toluene (300 mL), Pd(PPh3)4 (1.7 g, 1.47 mmol, 0.07 equiv) and 2-(tributylstannyl)-l,3-oxazole (8.6 g, 24.02 mmol, 1.16 equiv). The resulting solution was stirred overnight at 110 °C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 : 10). Purification afforded 6 g of 76.4 as a white solid.

Synthesis of compound 1-181. Into a 250-mL 3-necked round-bottom flask, was placed 76.4 (6 g, 7.43 mmol, 1.00 equiv), tetrahydrofuran (100 mL), TBAF (2.3 g, 8.80 mmol,

I .18 equiv). The resulting solution was stirred for 1 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (50: 1). This resulted in 3.4 g (80%) of Compound 1-181 as a white solid.

Purification: MS (ES): m/z 570 (M+H)+, 592 (M+Na)+.

1H NMR (300 MHz, DMSO- d6): δ 1.22-1.36 (m, 2H), 1.62 (m, 8H), 2.75 (s, 3H), 3.20-3.39 (m, 3H), 3.48-3.58 (m, 2H), 3.80 (s, 3H), 3.85-4.20 (m, 2H), 5.30 (m, 1H), 7.03 (m, 2H), 7.33-7.50 (m, 3H), 8.2 (s, 1H).

Figure imgf000193_0001

ndi molecul

Preparation of ND-630.1,4-dihydro-1-[(2R)-2-(2-methoxyphenyl)-2-[(tetrahydro-2H-pyran-4-yl)oxy]ethyl]-α,α,5-trimethyl-6-(2-oxazolyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-3(2H)-acetic acid, ND-630, was prepared as described (49)…….http://www.pnas.org/content/113/13/E1796.full.pdf
Harriman GC, Masse CE, Harwood HJ, Jr, Baht S, Greenwood JR (2013) Acetyl-CoA
carboxylase inhibitors and uses thereof. US patent publication US 2013/0123231.
CLIPS

The Liver Meeting 2015 – American Association for the Study of Liver Diseases (AASLD) – 2015 Annual Meeting,  San Francisco, CA, USA

Conference: 66th Annual Meeting of the American Association for the Study of Liver Diseases Conference Start Date: 13-Nov-2015

…candidates for minimizing IR injury in liver transplantation.Nimbus compounds targeting liver disease in rat modelsData were presented by Geraldine Harriman, from Nimbus Therapeutics, from rat models using acetyl-CoA carboxylase (ACC) inhibitors NDI-010976 (ND630) and N-654, which improved metabolic syndrome endpoints, decreased liver steatosis, decreased expression of inflammatory markers and improved fibrosis. The hepatotropic ACC inhibitor NDI-010976 had IC50 values of 2 and 7 nM for ACC1 and 2, respectively…

REFERENCES

November 13-17 2015
The Liver Meeting 2015 – American Association for the Study of Liver Diseases (AASLD) – 2015 Annual Meeting  San Francisco, CA, USA ,
WO-2014182943

WO-2014182951 

WO-2014182945

WO-2014182950 

Patent ID Date Patent Title
US2015203510 2015-07-23 ACC INHIBITORS AND USES THEREOF
US2013123231 2013-05-16 ACC INHIBITORS AND USES THEREOF

/////// ND 630, NDI 010976,  ND-630, NDI-010976, NIMBUS, GILEAD, 1434635-54-7

O=C(O)C(C)(C)N4C(=O)c1c(C)c(sc1N(C[C@H](OC2CCOCC2)c3ccccc3OC)C4=O)c5ncco5


Filed under: Uncategorized Tagged: 1434635-54-7, Gilead, ND 630, NDI 010976, NIMBUS

Perspectives on Anti-Glycan Antibodies Gleaned from Development of a Community Resource Database

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Abstract Image

Antibodies are used extensively for a wide range of basic research and clinical applications. While an abundant and diverse collection of antibodies to protein antigens have been developed, good monoclonal antibodies to carbohydrates are much less common. Moreover, it can be difficult to determine if a particular antibody has the appropriate specificity, which antibody is best suited for a given application, and where to obtain that antibody. Herein, we provide an overview of the current state of the field, discuss challenges for selecting and using antiglycan antibodies, and summarize deficiencies in the existing repertoire of antiglycan antibodies. This perspective was enabled by collecting information from publications, databases, and commercial entities and assembling it into a single database, referred to as the Database of Anti-Glycan Reagents (DAGR). DAGR is a publicly available, comprehensive resource for anticarbohydrate antibodies, their applications, availability, and quality

Monoclonal antibodies have transformed biomedical research and clinical care. In basic research, these proteins are used widely for a myriad of applications, such as monitoring/detecting expression of biomolecules in tissue samples, activating or antagonizing various biological pathways, and purifying antigens. To illustrate the magnitude and importance of the antibody reagent market, one commercial supplier sells over 50 000 unique monoclonal antibody clones. In a clinical setting, antibodies are used frequently as therapeutic agents and for diagnostic applications. As a result, monoclonal antibodies are a multibillion dollar industry, with antibody therapeutics estimated at greater than $40 billion annually, diagnostics at roughly $8 billion annually, and antibody reagents at $2 billion annually as of 2012

Perspectives on Anti-Glycan Antibodies Gleaned from Development of a Community Resource Database

Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, Maryland 21702, United States
ACS Chem. Biol., Article ASAP
DOI: 10.1021/acschembio.6b00244
Publication Date (Web): May 25, 2016
Copyright © 2016 American Chemical Society

ACS Editors’ Choice – This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.

http://pubs.acs.org/doi/full/10.1021/acschembio.6b00244

 

 

Jeffrey C. Gildersleeve, Ph.D.

Senior Investigator
Head, Chemical Glycobiology Section

The Gildersleeve group works at the interface of chemistry, glycobiology, and immunology. We use chemical approaches to 1) aid the design and development of cancer and HIV vaccines, 2) identify clinically useful biomarkers, and 3) better understand the roles of carbohydrates in cancer and HIV immunology. To facilitate these studies, we have developed a glycan microarray that allows high-throughput profiling of serum anti-glycan antibody populations.

Link to additional information about Dr. Gildersleeve’s research.

Areas of Expertise

1) glycan array technology, 2) cancer biomarkers, 3) cancer vaccines, 4) synthesis of carbohydrate antigens

Contact Info

Jeffrey C. Gildersleeve, Ph.D.
Center for Cancer Research
National Cancer Institute
Building 376, Room 208
Frederick, MD 21702-1201
Ph: 301-846-5699
gildersj@mail.nih.gov (link sends e-mail)

The Gildersleeve group works at the interface of chemistry, glycobiology, and immunology. We use chemical approaches to 1) aid the design and development of cancer and HIV vaccines, 2) identify clinically useful biomarkers, and 3) better understand the roles of carbohydrates in cancer and HIV immunology. To facilitate these studies, we have developed a glycan microarray that allows high-throughput profiling of serum anti-glycan antibody populations. A number of other groups have also developed glycan arrays; our array is unique in that we use multivalent neoglycoproteins as our array components. This format allows us to readily translate array results to other applications and affords novel approaches to vary glycan presentation.

The main focus of our current and future research is to study the roles of anti-glycan antibodies in the development, progression, and treatment of cancer. These projects are shedding new light on how cancer vaccines work and are uncovering new biomarkers for the early detection, diagnosis, and prognosis of cancer. In particular, we are studying immune responses induced by PROSTVAC-VF, a cancer vaccine in Phase III clinical trials for the treatment of advanced prostate cancer. In addition, we are identifying biomarkers for the early detection and prognosis of ovarian and lung cancer. These projects are highly collaborative in nature and are focused on translating basic research from the bench to the clinic. We rely heavily on glycan array technology to study immune responses to carbohydrates, and we continually strive to improve this technology. First, carbohydrate-protein interactions often involve formation of multivalent complexes. Therefore, presentation is a key feature of recognition. We have developed several new approaches to vary carbohydrate presentation on the surface of the array, including methods to vary glycan density and neoglycoprotein density. Second, we use synthetic organic chemistry to obtain a diverse set of tumor-associated carbohydrates and glycopeptides to populate our array.

Collaborations and Carbohydrate Microarray Screening. We are frequently asked to screen lectins, antibodies, and other entities on our array. Although we are not a core facility and do not provide screening services per se, we are happy to collaborate on many projects. Please contact Jeff Gildersleeve for more details.

Scientific Focus Areas:

Chemical Biology, Immunology

CBL's Eric Sterner wins NIH FARE Award

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CBL’s Eric Sterner wins NIH FARE Award

Dr. Eric Sterner, a postdoctoral CRTA Fellow in the Gilderlseeve Lab was presented with a FARE award for his abstract entitled, “Profiling Mutational Significance in Germline-to-Affinity Mature 3F8 Variants” in the NIH-wide FARE 2016 competition. This award is given to abstracts that are deemed outstanding based on scientific merit, originality, experimental design and overall quality and presentation. FARE 2016 is sponsored by the NIH Scientific Directors, the Office of Intramural Training & Education and FelCom. The FARE 2016 Award is a $1000 travel grant to attend and present this work at a scientific meeting within the United States.

 

Natalie Flanagan

Natalie Flanagan

Postbaccalaureate Fellow – Cancer Research Training Award (CRTA) at National Cancer Institute (NCI)

https://www.linkedin.com/in/natalie-flanagan-602a98109

Experience

Organic Chemistry Lab TA

University of Maryland

September 2014 – May 2015 (9 months)College Park, Maryland

– Ran on section of the Organic Chemistry I laboratory course for two semesters
– Worked with students in a laboratory setting and office hours to help them understand course materials and experimental procedures
– Worked with professors and other TAs to help develop and grade examinations

Summer Intern

Pfizer

June 2013 – August 2013 (3 months)Groton, Connecticut

– Used protein crystallization to research ligand binding in a protein kinase system
– Learned a variety of laboratory techniques, including: expression and purification of proteins, and various protein crystallization techniques
– Gained a basic knowledge for how to interpret electron density maps used in three-dimensional protein structure determination
– Presented my research project at an internal poster presentation

 

//////////Anti-Glycan Antibodies,  Gleaned,  Community Resource Database



Filed under: ANTIBODIES, Uncategorized Tagged: Anti-Glycan Antibodies, Gleaned, Community Resource Database

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