ENCORAFENIB, エンコラフェニブ

UNII:8L7891MRB6

Formula:C22H27ClFN7O4S, Average: 540.01

1269440-17-6

• BRAFTOVI
• NVP-LGX818
• NVP-LGX-818-NXA
• NVP-LGX818-NXA
• ENCORAFENIB [USAN]
• ENCORAFENIB [WHO-DD]
• ENCORAFENIB
• ENCORAFENIB [INN]
• METHYL N-((2S)-1-((4-(3-(5-CHLORO-2-FLUORO-3-(METHANESULFONAMIDO)PHENYL)(-1-(PROPAN-2-YL)-1H-PYRAZOL-4-YL(PYRIMIDIN-2-YL)AMINO)PROPAN-2-YL)CARBAMATE
• CARBAMIC ACID, N-((1S)-2-((4-(3-(5-CHLORO-2-FLUORO-3-((METHYLSULFONYL)AMINO)PHENYL)-1-(1-METHYLETHYL)-1H-PYRAZOL-4-YL)-2-PYRIMIDINYL)AMINO)-1-METHYLETHYL)-, METHYL ESTER
• LGX818
• LGX-818

Encorafenib, also known as BRAFTOVI, is a kinase inhibitor. Encorafenib inhibits BRAF gene, which encodes for B-raf protein, which is a proto-oncogene involved in various genetic mutations ^Label. This protein plays a role in regulating the MAP kinase/ERK signaling pathway, which impacts cell division, differentiation, and secretion. Mutations in this gene, most frequently the V600E mutation, are the most commonly identified cancer-causing mutations in melanoma, and have been isolated in various other cancers as well, including non-Hodgkin lymphoma, colorectal cancer, thyroid carcinoma, non-small cell lung carcinoma, hairy cell leukemia and adenocarcinoma of the lung ⁶.

On June 27, 2018, the Food and Drug Administration approved encorafenib and Binimetinib(BRAFTOVI and MEKTOVI, Array BioPharma Inc.) in combination for patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-approved test ^Label.

Array Biopharma  (a wholly owned subsidiary of  Pfizer ), under license from  Novartis , and licensees  Pierre Fabre  and  Ono Pharmaceutical  have developed and launched the B-Raf kinase inhibitor encorafenib . In January 2020, the US FDA’s Orange Book was seen to list encorafenib patents such as US8946250 , US8501758 , US9314464 and US9763941 , expiring in the range of 2029-2032. At that time Orange Book also reported that encorafenib as having NCE exclusivity expiring on July 27, 2023.

Encorafenib (trade name Braftovi) is a drug for the treatment of certain melanomas. It is a small molecule BRAF inhibitor ^[1] that targets key enzymes in the MAPK signaling pathway. This pathway occurs in many different cancers including melanoma and colorectal cancers.^[2] The substance was being developed by Novartis and then by Array BioPharma. In June 2018, it was approved by the FDA in combination with binimetinib for the treatment of patients with unresectable or metastatic BRAF V600E or V600K mutation-positive melanoma.^[3][4]

The most common (≥25%) adverse reactions in patients receiving the drug combination were fatigue, nausea, diarrhea, vomiting, abdominal pain, and arthralgia.^[3]

Indication

Used in combination with Binimetinib in metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-approved test ⁵.

Associated Conditions

• Metastatic Melanoma
• Unresectable Melanoma

Pharmacodynamics

Encorafenib has shown improved efficacy in the treatment of metastatic melanoma ³.

Encorafenib, a selective BRAF inhibitor (BRAFi), has a pharmacologic profile that is distinct from that of other clinically active BRAFis ⁷.

Once-daily dosing of single-agent encorafenib has a distinct tolerability profile and shows varying antitumor activity across BRAFi-pretreated and BRAFi-naïve patients with advanced/metastatic stage melanoma ⁷.

Mechanism of action

Encorafenib is a kinase inhibitor that specifically targets BRAF V600E, as well as wild-type BRAF and CRAF while tested with in vitro cell-free assays with IC50 values of 0.35, 0.47, and 0.3 nM, respectively. Mutations in the BRAF gene, including BRAF V600E, result in activated BRAF kinases that mahy stimulate tumor cell growth. Encorafenib is able to bind to other kinases in vitro including JNK1, JNK2, JNK3, LIMK1, LIMK2, MEK4, and STK36 and significantly reduce ligand binding to these kinases at clinically achievable concentrations (≤ 0.9 μM) ^Label.

In efficacy studies, encorafenib inhibited the in vitro cell growth of tumor cell lines that express BRAF V600 E, D, and K mutations. In mice implanted with tumor cells expressing the BRAF V600E mutation, encorafenib induced tumor regressions associated with RAF/MEK/ERK pathway suppression ^Label.

Encorafenib and binimetinib target two different kinases in the RAS/RAF/MEK/ERK pathway. Compared with either drug alone, co-administration of encorafenib and binimetinib result in greater anti-proliferative activity in vitro in BRAF mutation-positive cell lines and greater anti-tumor activity with respect to tumor growth inhibition in BRAF V600E mutant human melanoma xenograft studies in mice. In addition to the above, the combination of encorafenib and binimetinib acted to delay the emergence of resistance in BRAF V600E mutant human melanoma xenografts in mice compared with the administration of either drug alone ^Label.

Pharmacology

Encorafenib acts as an ATP-competitive RAF kinase inhibitor, decreasing ERK phosphorylation and down-regulation of CyclinD1.^[5]This arrests the cell cycle in G1 phase, inducing senescence without apoptosis.^[5] Therefore it is only effective in melanomas with a BRAF mutation, which make up 50% of all melanomas.^[6] The plasma elimination half-life of encorafenib is approximately 6 hours, occurring mainly through metabolism via cytochrome P450 enzymes.^[7]

Clinical trials

Several clinical trials of LGX818, either alone or in combinations with the MEK inhibitor MEK162,^[8] are being run. As a result of a successful Phase Ib/II trials, Phase III trials are currently being initiated.^[9]

History

Approval of encorafenib in the United States was based on a randomized, active-controlled, open-label, multicenter trial (COLUMBUS; NCT01909453) in 577 patients with BRAF V600E or V600K mutation-positive unresectable or metastatic melanoma.^[3] Patients were randomized (1:1:1) to receive binimetinib 45 mg twice daily plus encorafenib 450 mg once daily, encorafenib 300 mg once daily, or vemurafenib 960 mg twice daily.^[3] Treatment continued until disease progression or unacceptable toxicity.^[3]

The major efficacy measure was progression-free survival (PFS) using RECIST 1.1 response criteria and assessed by blinded independent central review.^[3] The median PFS was 14.9 months for patients receiving binimetinib plus encorafenib, and 7.3 months for the vemurafenib monotherapy arm (hazard ratio 0.54, 95% CI: 0.41, 0.71, p<0.0001).^[3] The trial was conducted at 162 sites in Europe, North America and various countries around the world.^[4]

SYN

PATENT

WO2010010154 , expiry , EU states,  2029,  US in 2030 with US154 extension.

WO 2011025927

WO 2016089208

Patent

WO-2020011141

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020011141&tab=FULLTEXT&_cid=P20-K5QFFQ-43376-1

Novel deuterated analogs of diarylpyrazole compounds, particularly encorafenib are B-RAF and C-RAF kinase inhibitors, useful for treating proliferative diseases such as melanoma and colorectal cancer. Family members of the product case, WO2010010154 , expire in most of the EU states until 2029 and will expire in the US in 2030 with US154 extension. In January 2020, the US FDA’s Orange Book was seen to list encorafenib patents such as US8946250 , US8501758 , US9314464 and US9763941 , expiring in the range of 2029-2032. At that time Orange Book also reported that encorafenib as having NCE exclusivity expiring on July 27, 2023.

PAPER

European journal of cancer (Oxford, England : 1990) (2018), 88, 67-76.

References

External links

• “Encorafenib”. Drug Information Portal. U.S. National Library of Medicine.

1. Li Z, Jiang K, Zhu X, Lin G, Song F, Zhao Y, Piao Y, Liu J, Cheng W, Bi X, Gong P, Song Z, Meng S: Encorafenib (LGX818), a potent BRAF inhibitor, induces senescence accompanied by autophagy in BRAFV600E melanoma cells. Cancer Lett. 2016 Jan 28;370(2):332-44. doi: 10.1016/j.canlet.2015.11.015. Epub 2015 Nov 14. [PubMed:26586345]
2. Koelblinger P, Thuerigen O, Dummer R: Development of encorafenib for BRAF-mutated advanced melanoma. Curr Opin Oncol. 2018 Mar;30(2):125-133. doi: 10.1097/CCO.0000000000000426. [PubMed:29356698]
3. Moschos SJ, Pinnamaneni R: Targeted therapies in melanoma. Surg Oncol Clin N Am. 2015 Apr;24(2):347-58. doi: 10.1016/j.soc.2014.12.011. Epub 2015 Jan 24. [PubMed:25769717]
4. Dummer R, Ascierto PA, Gogas HJ, Arance A, Mandala M, Liszkay G, Garbe C, Schadendorf D, Krajsova I, Gutzmer R, Chiarion-Sileni V, Dutriaux C, de Groot JWB, Yamazaki N, Loquai C, Moutouh-de Parseval LA, Pickard MD, Sandor V, Robert C, Flaherty KT: Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2018 May;19(5):603-615. doi: 10.1016/S1470-2045(18)30142-6. Epub 2018 Mar 21. [PubMed:29573941]
5. FDA approves encorafenib and binimetinib in combination for unresectable or metastatic melanoma with BRAF mutations [Link]
6. BRAF B-Raf proto-oncogene, serine/threonine kinase [ Homo sapiens (human) ] [Link]
7. Phase I Dose-Escalation and -Expansion Study of the BRAF Inhibitor Encorafenib (LGX818) in Metastatic BRAF-Mutant Melanoma [Link]
8. Encorafenib FDA label [File]
9. Encorafenib review [File]

Encorafenib

Clinical data
Trade names	Braftovi
Other names	LGX818
AHFS/Drugs.com	Monograph
MedlinePlus	a618040
License data	US DailyMed: Encorafenib
Routes of administration	Oral
Drug class	Antineoplastic Agents
ATC code	L01XE46 (WHO)
Legal status
Legal status	US: ℞-only
Identifiers
IUPAC name[show]
CAS Number	1269440-17-6
PubChem CID	50922675
DrugBank	DB11718
ChemSpider	28536139
UNII	8L7891MRB6
KEGG	D11053
ChEMBL	ChEMBL3301612
CompTox Dashboard (EPA)	DTXSID00155347
Chemical and physical data
Formula	C22H27ClFN7O4S
Molar mass	540.011 g/mol g·mol−1
3D model (JSmol)	Interactive image
SMILES[hide] C[C@@H](CNc1nccc(n1)c2cn(nc2c3cc(cc(c3F)NS(=O)(=O)C)Cl)C(C)C)NC(=O)OC

///////////ENCORAFENIB, 1269440-17-6, BRAFTOVI, NVP-LGX818, LGX818, LGX 818, エンコラフェニブ  ,

COC(=O)N[C@@H](C)CNc1nccc(n1)c2cn(nc2c3cc(Cl)cc(NS(=O)(=O)C)c3F)C(C)C

patent

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Tranilast

• Molecular FormulaC₁₈H₁₇NO₅
• Average mass327.331 Da

Tranilast (INN, brand name Rizaben) is an antiallergic drug. It was developed by Kissei Pharmaceuticals and was approved in 1982 for use in Japan and South Korea for bronchial asthma. Indications for keloid and hypertrophic scar were added in the 1980s.

Kissei  has developed and launched tranilast in Japan and South Korea for the treatment of allergic rhinitis, asthma and atopic dermatitis. Kissei, in collaboration with  GlaxoSmithKline  was additionally developing tranilast for the prevention of restenosis following percutaneous transluminal coronary angioplasty.

Medical uses

It is used Japan, South Korea, and China to treat asthma, keloid scars, and hypertrophic scars, and as an ophthalmic solution for allergic pink eye.^[1]

It should not be taken women who are or might become pregnant, and it is secreted in breast milk.^[1]

Interactions

People who are taking warfarin should not also take tranilast, as they interact.^[1] It appears to inhibit UGT1A1 so will interfere with metabolism of drugs that are affected by that enzyme.^[1]

Adverse effects

When given systemically, tranilast appears to cause liver damage; in a large well-conducted clinical trial it caused elevated transaminases three times the upper limit of normal in 11 percent of patients, as well as anemia, kidney failure, rash, and problems urinating.^[1]

Given systemically it inhibits blood formation, causing leukopenia, thrombocytopenia, and anemia.^[1]

Society and culture

As of March 2018 it was marketed in Japan, China, and South Korea under the brand names Ao Te Min, Arenist, Brecrus, Garesirol, Hustigen, Krix, Lumios, Rizaben, Tramelas, Tranilast and it was marketed as a combination drug with salbutamol under the brand name Shun Qi.^[2]

In 2016 the FDA proposed that tranilast be excluded from the list of active pharmaceutical ingredients that compounding pharmacies in the US could formulate with a prescription.^[1]

Pharmacology

It appears to work by inhibiting the release of histamine from mast cells; it has been found to inhibit proliferation of fibroblasts but its biological target is not known.^[3] It has been shown to inhibit the release of many cytokines in various cell types, in in vitro studies.^[3] It has also been shown to inhibit NALP3 inflammasome activation and is being studied as a treatment for NALP3-driven inflammatory diseases.^[4]

Chemistry

Tranilast is an analog of a metabolite of tryptophan, and its chemical name is 3′,4′-dimethoxycinnamoyl) anthranilic acid (N-5′).^[3]

It is almost insoluble in water, easily soluble in dimethylsulfoxide, soluble in dioxane, and very slightly soluble in ether. It is photochemically unstable in solution.^[3]

Orally active anti-allergic agent. Prepn: K. Harita et al., DE 2402398; idem, US 3940422 (1974, 1976 both to Kissei).

Y. Kamijo, M. Kobayashi, and A. Ajisawa, Jpn. Kokai, 77/83,428 (1977) via Chem. Abstr.,

88:6,569f (1978).

Research

After promising results in three small clinical trials, tranilast was studied in a major clinical trial (the PRESTO trial) by SmithKline Beecham in partnership with Kissei for prevention of restenosis after percutaneous transluminal coronary revascularization,^[5] but was not found effective for that application.^[1][6]

As of 2016, Altacor was developing a formulation of tranilast to prevent of scarring following glaucoma surgery and had obtained an orphan designation from the EMA for this use.^[7][8]

History

It was developed by Kissei and first approved in Japan and South Korea for asthma in 1982, and approved uses for keloid and hypertrophic scars were added later in the 1980s.^[3]

PATENT

tranilast product case US03940422 , expired in all the regional territories.

PATENT

WO2013144916 claiming tranilast complexes and cocrystals with nicotinamide, saccharin, gentisic acid, salicylic acid, urea, 4-aminobenzoic acid and 2,4-dihydroxybenzoic acid

Patent

WO-2020035546

Nuformix Ltd

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020035546&tab=PCTDESCRIPTION&_cid=P11-K75NGV-11408-1

Novel crystalline forms of tranilast or its salts as histamine H1 receptor antagonist useful for treating allergy, allergic rhinitis and atopic dermatitis.

Tranilast, (2-[[3-(3,4-dimethoxyphenyl)-l-oxo-2-propenyl]amino] benzoic acid, shown below), was originally developed as an anti-allergy drug due to its ability to inhibit the release of inflammatory mediators, such as histamine, from mast cells and basophils (P. Zampini. IntJ Immunopharmacol. 1983;

Tranilast

Tranilast has been marketed in Japan, China and South Korea by Kissei Pharmaceutical Co. Ltd, for allergic conditions such as allergic conjunctivitis, bronchial asthma, allergic rhinitis and atopic dermatitis, under the Rizaben^® brand name for more than thirty years. More recently tranilast has also been shown to have anti-proliferative properties. Tranilast was shown to inhibit the proliferation of fibroblasts and suppress collagen synthesis (M. Isaji. Biochem Pharmacol. 1987; 36: 469-474) and also to inhibit the transformation of fibroblasts to myofibroblasts and their subsequent contraction (M. Isaji. Life Sci. 1994; 55: 287-292). This additional behaviour led to tranilast gaining additional approval for the treatment of keloids and hypertrophic scars.

[004] Over recent years many researchers have explored the anti-proliferative effects of tranilast to assess its potential in fibrotic and cancerous conditions. Its anti-proliferative action is believed to be due to its ability to inhibit transforming growth factor beta (TGF-b) (H. Suzawa. Jpn J Pharmacol. 1992 Oct; 60(2): 91-96). Fibrosis is a condition that can affect most organs of the body and fibroblast proliferation, differentiation and collagen synthesis are known to be key factors in the progression of most types of fibrosis. Tranilast has been shown in-vivo to have potential beneficial effects in

numerous fibrotic conditions. Tranilast has been shown in-vivo to have potential in lung fibrosis (M. Kato. Eur RespirJ. 2013; 42(57): 2330), kidney fibrosis (DJ Kelly, J Am Soc Nephrol. 2004; 15(10): 2619-29), cardiac fibrosis (J Martin, Cardiovasc Res. 2005; 65(3): 694-701), ocular fibrosis (M J Moon, BMC Opthalmol. 2016; 16: 166) and liver fibrosis (M Uno, Hepatology. 2008; 48(1): 109-18.

[005] Tranilast’s anti-tumor action has also recently been demonstrated, in-vitro and in-vivo. Tranilast has been shown to inhibit the proliferation, apoptosis and migration of several cell lines including breast cancer (R. Chakrabarti. Anticancer Drugs. 2009 Jun; 20(5): 334-45) and prostate cancer (S. Sato. Prostate. 2010 Feb; 70(3): 229-38) cell lines. In a study of mammary carcinoma in mice tranilast was found to produce a significant reduction in metastasis (R. Chakrabarti. Anticancer Drugs. 2009 Jun; 20(5): 334-45). In a pilot study in humans, tranilast was shown to have the potential to improve the prognosis of patients with advanced castration-resistant prostate cancer (K. Izumi. Anticancer Research. 2010 Jul; 30: 73077-81). In-vitro studies also showed the therapeutic potential of tranilast in glioma (M Platten. IntJ Cancer. 2001; 93:53-61), pancreatic cancer (M Hiroi, J Nippon Med Sch. 2002; 69: 224-234) and gastric carcinoma (M Yashiro, Anticancer Res. 2003; 23: 3899-3904).

[006] Given the wide range of fibrotic conditions and cancers for which tranilast could have a potential therapeutic benefit, as well as the different patient types and specific areas of the body requiring treatment, it is anticipated that patients would benefit from having multiple delivery methods for the administration of tranilast so as to best suit the patient’s needs. The pharmaceutical compositions could include, for example, a solid oral dosage, a liquid oral dosage, an injectable composition, an inhalable composition, a topical composition or a transdermal composition.

[007] Kissei Pharmaceutical Co. Ltd explored the anti-proliferative effect of tranilast in the prevention of restenosis associated with coronary intervention. In a Phase II clinical study Kissei found that the current approved dose of tranilast (300 mg/day) was insufficient to prevent restenosis and that a higher dose of 600 mg/day was needed to achieve a decrease in restenosis rates (H. Tamai, Am Heart J.1999; 138(5): 968-75). However, it was found that a 600 mg daily dosage can result in a ten-fold inter-patient variation in plasma concentrations of the drug (30-300 pmol/L) (H Kusa ma. Atherosclerosis. 1999; 143: 307-313) and in the Phase III study of tranilast for the prevention of restenosis the dose was further increased to 900mg daily (D Holmes, Circulation. 2002; 106(10): 1243-1250).

[008] The marketed oral form of tranilast (Rizaben^®) contains tranilast in its pure crystalline form. Crystalline tranilast has extremely low aqueous solubility (solubility of 14.5 pg/ml in water and 0.7 pg/ml in pH 1.2 buffer solution (Society of Japanese Pharmacopoeia. 2002)). Whilst, high energy amorphous forms are often used as a means of improving the solubility of poorly soluble drug

compounds, literature shows that an amorphous form of tranilast is not completely photostable in the solid state and that it undergoes photodegradation on storage when exposed to light (S. Onoue. EurJ Pharm Sci. 2010; 39: 256-262).

[009] It is expected that the very low solubility of tranilast is a limiting factor in the oral bioavailability of the drug. Given the limited time any drug has to firstly dissolve in the

gastrointestinal tract and then be absorbed into the bloodstream, this issue will become even more limiting as the oral dose of tranilast is increased. The poor solubility of tranilast is also possibly a key factor in the high inter-patient variability reported for higher dose tranilast pharmacokinetics. As a BCS class II drug (low solubility/high permeability) it is expected that absorption from the gastrointestinal tract is hampered by the dissolution rate of the drug in gastrointestinal media as well as its overall solubility. For treatment of chronic proliferative diseases such as fibrosis and cancer it is vital for the delivery method of a drug to produce consistent, predictable plasma levels that are maintained above the minimum effective concentration. To achieve efficacious oral delivery of tranilast at higher doses there is a need for new solid forms of the drug with both high solubility and rapid dissolution rates.

[010] Given the severity of conditions involving cancer or fibrosis there is also a need for systemic treatment options by which tranilast can be delivered by healthcare specialists that do not require the patient to swallow solid oral dosage forms. Alternative dosage forms suitable for these needs could include, for example, injectable compositions, liquid oral formulations or nebulized inhaled formulations. These would require a liquid formulation of tranilast suitable for systemic delivery. [Oil] Given the potential of tranilast to treat ocular diseases, such as allergic conjunctivitis, Kissei Pharmaceutical Co. Ltd recognised the need to develop an eye drop formulation of tranilast for localised treatment. However, as well as having very low aqueous solubility, tranilast is also photochemically unstable when stored in solution, resulting in significant degradation (N Hori, Chem. Pharm. Bull. 1999; 47(12): 1713-1716). Therefore, the only way Kissei were able to achieve an eye drop liquid composition of tranilast was to use both solubilising and stabilising agents in the formulation (US Patent 5356620). The resulting 0.5% (w/v) eye drop formulation is currently also marketed under the Rizaben^® brand name. However, the focus of this formulation and of the subsequent research that has attempted to produce alternative solution formulations of tranilast has always been solely on external delivery of tranilast using compositions such as eye drops and skin ointments etc. None of the liquid formulations of tranilast previously described have been produced for systemic delivery such as for oral or IV delivery. Excipients used in the previously reported external preparations are not suitable for systemic delivery. Also, despite the successful

development of an eye drop formulation of tranilast, the package insert of the marketed Rizaben^® eye drops states that the product should not be stored in a refrigerator as crystals may precipitate.

[012] Thus, there remains a need for aqueous pharmaceutical compositions of tranilast suitable for systemic delivery. Given the potential photochemical degradation issue of long term storage of tranilast in solution and also the disadvantage of the larger storage facilities needed to store bulkier solution based formulations it would also be advantageous to develop a stable highly soluble solid form of tranilast that can be quickly dissolved at the time of treatment by the patient or healthcare provider to produce the required liquid formulation.

[013] Following efforts to make a liquid formulation of tranilast, Kissei made the statement that tranilast and pharmaceutically acceptable salts thereof are too insoluble in water to prepare an aqueous solution (US Patent 5356620). Since that US patent the only crystalline pharmaceutically acceptable salt to have been published is the sodium salt (N Geng, Cryst. Growth Des. 2013; 13: 3546-3553). In line with the findings of Kissei the authors of this paper stated that the apparent solubility of the crystalline tranilast sodium salt is even less than that of pure tranilast. Also, when they performed a dissolution study of tranilast in a sodium containing media they found that as the tranilast dissolved it gradually precipitated out of solution as its sodium salt indicating that the sodium salt has a lower thermodynamic solubility than the pure drug. The authors of this paper also successfully prepared the non-pharmaceutically acceptable crystalline cytosine salt of tranilast. Despite this crystalline cytosine salt showing approximately a two-fold solubility improvement over pure crystalline tranilast, not only would this crystalline cytosine salt not be suitable for systemic delivery to a patient due to cytosine not having FDA acceptability but this improvement in solubility would not be great enough to produce high dose tranilast liquid formulations such as an injectable formulation.

[014] Patent application EP1946753 discloses an attempt to prepare an external preparation of tranilast and claims the preparation of ionic liquid salts of tranilast with organic amines. The inventors claim that blending tranilast with the organic amine results in a liquid form. This application does not disclose the formation of any solid state, crystalline tranilast salts with organic amines. They demonstrate that these ionic liquid forms of tranilast have higher solubility in solvents suitable for external application to the skin and that these preparations have higher photostability than pure tranilast in the same formulation. However, this improved photostability still results in a significant proportion of the tranilast being photo-degraded and would not be suitable for long term storage. Also, the solvents used for preparation of these ionic liquid salt formulations are not suitable for internal delivery of tranilast. Moreover, there is no mention in EP1946753 of improved solubility in aqueous or bio-relevant media.

PATENT

US20150119428

https://patents.google.com/patent/US20150119428

• Tranilast, (2-[[3-(3,4-dimethoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid), shown below, is a therapeutic agent that exhibits an anti-allergic effect. It has been shown to inhibit the release of inflammatory mediators, such as histamine, from mast cells and basophils (P. Zampini. Int J Immunopharmacol. 1983; 5(5): 431-5). Tranilast has been used as an anti-allergic treatment, for several years in Japan and South Korea, for conditions such as allergic conjunctivitis, bronchial asthma, allergic rhinitis and atopic dermatitis.
• [0004]
  Tranilast is currently marketed in Japan and South Korea by Kissei Pharmaceutical Co. Ltd under the Rizaben® brand name. As well as displaying an anti-allergic effect tranilast has been shown to possess anti-proliferative properties. Tranilast was found to inhibit the proliferation of fibroblasts and suppress collagen synthesis (M. Isaji. Biochem Pharmacol. 1987; 36: 469-474) and also to inhibit the transformation of fibroblasts to myofibroblasts and their subsequent contraction (M. Isaji. Life Sci. 1994; 55: 287-292). On the basis of these effects tranilast is now also indicated for the treatment of keloids and hypertrophic scars. Its anti-fibrotic action is believed to be due to its ability to inhibit transforming growth factor beta (TGF-β) (H. Suzawa. Jpn J Pharmacol. 1992 October; 60(2): 91-96). TGF-β induced fibroblast proliferation, differentiation and collagen synthesis are known to be key factors in the progression of idiopathic pulmonary fibrosis and tranilast has been shown in-viva to have potential in the treatment of this chronic lung disease (T. Jiang. Afr J Pharm Pharmaco. 2011; 5(10): 1315-1320). Tranilast has also been shown in-vivo to be have potential beneficial effects in the treatment of airway remodelling associated with chronic asthma (S. C. Kim. J Asthma 2009; 46(9): 884-894.
• [0005]
  It has been reported that tranilast also has activity as an angiogenesis inhibitor (M. Isaji. Br. J Pharmacol. 1997; 122(6): 1061-1066). The results of this study suggested that tranilast may be beneficial for the treatment of angiogenic diseases such as diabetic retinopathy and age related macular degeneration. As well as showing inhibitory effects on mast cells and fibroblasts, tranilast has also demonstrated an ability to diminish tumor necrosis factor-alpha (TNF-α) from cultured macrophages (H. O. Pae. Biochem Biophys Res Commun. 371: 361-365) and T-cells (M. Platten. Science. 310: 850-855), and inhibited NF-kB-dependent transcriptional activation in endothelial cells (M. Spieker. Mol Pharmacol. 62: 856-863). Recent studies have revealed that tranilast attenuates inflammation and inhibits bone destruction in collagen induced arthritis in mice suggesting the possible usefulness of tranilast in the treatment of inflammatory conditions such as arthritis (N. Shiota. Br. Pharmacol. 2010; 159 (3): 626-635).
• [0006]
  As has recently been demonstrated, in-vitro and in-vivo, tranilast also possesses an anti-tumor action. Tranilast has been shown to inhibit the proliferation, apoptosis and migration of several cell lines including breast cancer (R. Chakrabarti. Anticancer Drugs. 2009 June; 20(5): 334-45) and prostate cancer (S. Sato. Prostate. 2010 February; 70(3): 229-38) cell lines. In a study of mammary carcinoma in mice tranilast was found to produce a significant reduction in metastasis (R. Chakrabarti. Anticancer Drugs. 2009 June; 20(5): 334-45). In a pilot study in humans, tranilast was shown to have the potential to improve the prognosis of patients with advanced castration-resistant prostate cancer (K. Izurni. Anticancer Research. 2010 July; 30: 73077-81).
• [0007]
  It has been reported that tranilast has the ability to induce or enhance neurogenesis and, therefore, could be used as an agent to treat neuronal conditions such as cerebral ischernia, glaucoma, multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer’s disease, neurodegenerative trinucleotide repeat disorders, neurodegenerative lyosomal storage diseases, spinal cord injury and trauma, dementia, schizophrenia and peripheral neuropathy (A. Schneider. EP2030617).
• [0008]
  Tranilast’s beneficial properties have been reported to have utility in several ocular conditions. Tranilast is currently approved in Japan and Korea far the treatment of allergic conjunctivitis. WO2010137681 claims the use of tranilast as a prophylactic or therapeutic agent for the treatment of retinal diseases. The anti-fibrotic properties of tranilast have been reported to be of benefit in maintaining the filtering blob during glaucoma surgery and this has been demonstrated in a pilot study in humans (E. Chihara.J Glaucoma. 1999; 11(2): 127-133). There have also been several reported cases of the beneficial use of tranilast in the prevention of postoperative recurrence of pterygium (C. Fukui. Jap J Opthalmol. 1999; 12: 547-549). Tsuji recently reported that tranilast may be beneficial not only in the prevention of ptergium recurrence, but also for the inhibition of symblepharon and granuloma formation (A. Tsuji. Tokai J Exp Clin Med. 2011; 36(4): 120-123). Collectively it has been demonstrated that tranilast possesses anti-allergic, anti-fibrotic, anti-inflammatory, anti-tumor, neurogenesis enhancing end angiogenesis inhibitory properties and as such may be useful for the treatment of diseases associated with such properties.
• [0009]
  Tranilast occurs as a yellow crystalline powder that is identified by CAS Registry Number: 53902-12-8. As is typical of cinnamic acid derivatives (G. M. J. Schmidt J Chem. Soc. 1964: 2000) tranilast is photochemically unstable when in solution, tranforming into cis-isomer and dimer forms on exposure to light (N. Hori. Cehm Pharm Bull. 1999; 47: 1713-1716). Although pure crystalline tranilast is photochemically stable in the solid state it is practically insoluble in water (14.5 μg/ml) and acidic media (0.7 μg/ml in pH 1.2 buffer solution) (Society of Japanese Pharmacopoeia. 2002). Although tranilast has shown activity in various indications, it is possible that the therapeutic potential of the drug is currently limited by its poor solubility and photostability. High energy amorphous forms are often used as a means of improving the solubility of poorly soluble APIs, however, literature shows that amorphous solid dispersions of tranilast are not completely photostable in the solid state and that they undergo photodegradation on storage when exposed to light (S. Onoue. Eur J Pharm Sci. 2010; 39: 256-262). US20110136835 describes a combination of tranilast and allopurinol and its use in the treatment of hyperuricemia associated with gout and has one mention of a “co-crystal form”, but lacks any further description or characterization.

Patent

References

Tranilast

Clinical data
AHFS/Drugs.com	International Drug Names
Routes of administration	Oral
ATC code	none
Legal status
Legal status	US: Not FDA approved In general: ℞ (Prescription only)
Identifiers
IUPAC name[show]
CAS Number	53902-12-8
PubChem CID	5282230
IUPHAR/BPS	6326
ChemSpider	4445411
UNII	HVF50SMY6E
ChEBI	CHEBI:77572
ChEMBL	ChEMBL415324
CompTox Dashboard (EPA)	DTXSID7023693
ECHA InfoCard	100.150.125
Chemical and physical data
Formula	C18H17NO5
Molar mass	327.336 g·mol−1
3D model (JSmol)	Interactive image
SMILES[hide] COC1=C(C=C(C=C1)C=CC(=O)NC2=CC=CC=C2C(=O)O)OC
InChI[hide] InChI=1S/C18H17NO5/c1-23-15-9-7-12(11-16(15)24-2)8-10-17(20)19-14-6-4-3-5-13(14)18(21)22/h3-11H,1-2H3,(H,19,20)(H,21,22)/b10-8+ Key:NZHGWWWHIYHZNX-CSKARUKUSA-N

///////////////Tranilast,  Rizaben, antiallergic,  Kissei Pharmaceuticals,  Japan, South Korea,  bronchial asthma,  keloid,  hypertrophic scar

LANRAPLENIB

GS-9876

Phase II, GILEAD

Imidazo(1,2-a)pyrazin-8-amine, 6-(6-amino-2-pyrazinyl)-N-(4-(4-(3-oxetanyl)-1-piperazinyl)phenyl)-

6-(6-Aminopyrazin-2-yl)-N-(4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)imidazo|1,2-a]pyrazin-8-amine

6-(6-Amino-2-pyrazinyl)-N-(4-(4-(3-oxetanyl)-1-piperazinyl)phenyl)imidazo(1,2-a)pyrazin-8-amine

Lanraplenib (GS-9876) is a highly selective and orally active SYK inhibitor (IC₅₀=9.5 nM) in development for the treatment of inflammatory diseases. Lanraplenib (GS-9876) inhibits SYK activity in platelets via the glycoprotein VI (GPVI) receptor without prolonging bleeding time (BT) in monkeys or humans.

Lanraplenib succinate

1800047-00-0

UNII-QJ2PS903VZ

QJ2PS903VZ

GS-SYK Succinate

1241.3 g/mol, C₅₈H₆₈N₁₈O₁₄

6-(6-aminopyrazin-2-yl)-N-[4-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]imidazo[1,2-a]pyrazin-8-amine;butanedioic acid

PAPER

https://pubs.acs.org/doi/10.1021/acsmedchemlett.9b00621

https://pubs.acs.org/doi/suppl/10.1021/acsmedchemlett.9b00621/suppl_file/ml9b00621_si_001.pdf

Spleen tyrosine kinase (SYK) is a critical regulator of signaling in a variety of immune cell types such as B-cells, monocytes, and macrophages. Accordingly, there have been numerous efforts to identify compounds that selectively inhibit SYK as a means to treat autoimmune and inflammatory diseases. We previously disclosed GS-9973 (entospletinib) as a selective SYK inhibitor that is under clinical evaluation in hematological malignancies. However, a BID dosing regimen and drug interaction with proton pump inhibitors (PPI) prevented development of entospletinib in inflammatory diseases. Herein, we report the discovery of a second-generation SYK inhibitor, GS–9876 (lanraplenib), which has human pharmacokinetic properties suitable for once-daily administration and is devoid of any interactions with PPI. Lanraplenib is currently under clinical evaluation in multiple autoimmune indications.

Step 6. 6-(6-Aminopyrazin-2-yl)-N-(4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)imidazo|1,2-a]pyrazin-8-amine (39). To a solution of tert-butyl(6-(6-(bis(tert-butoxycarbonyl)amino)pyrazm-2-yl)imidazo[1,2-a]pyrazin-8-yl)(4-(4-(oxetan-3-yl)piperazin1yl)phenyl)carbamate 45 (200 mg, 0.269 mmol) in DCM (2 ml) was added TFA (0.5 ml, 6.578 mmol). The reaction was stirred at room temperature for 16h, treated with saturated sodium bicarbonate, extracted with EtOAc, and purified on silica gel, eluting with 5%MeOH / EtOAc to 20%MeOH / EtOAc. The desired fractions were combined and concentrated to provide 100 mg (83% yield) of the title compound 39. m/z calcd for C23H25N9O [M+H] + 444.23, found LCMS-ESI+ (m/z): [M+H] + 444.20. 1H NMR (300 MHz d6-DMSO) δ: 9.5 (s,lH), 8.588 (s, 1H), 8.47 (s, 1H), 8.12 (d, 1H), 7.95-7.92 (d5 2H), 7.88 (s, 1H), 7.62 (s, 1H), 6.99-6.96 (d, 2H), 6.46 (s, 2H), 4.57- 4.53 (m, 2H), 4.48-4.44 (m, 2H), 3.43 (m, 1H), 3.15-3.12 (m, 4H), 2.41- 2.38 (m, 4H).

MORE SYNTHESIS COMING, WATCH THIS SPACE…………………..

SYNTHESIS

PATENT

WO 2015100217

WO 2016010809

PATENT

WO 2016172117

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016172117

Protein kinases, the largest family of human enzymes, encompass well over 500 human proteins. Spleen Tyrosine Kinase (Syk) is a member of the Syk family of tyrosine kinases, and is a regulator of early B-cell development as well as mature B-cell activation, signaling, and survival.

Acute Graft Versus Host Disease (aGVHD), also known as fulminant Graft Versus Host Disease, generally presents symptoms within the first 100 days following allogenic hematopoietic stem cell transplantation and is generally characterized by selective damage to the skin, liver, mucosa, and gastrointestinal tract. Chronic Graft Versus Host Disease (cGVHD) occurs in recipients of allogeneic hematopoietic stem cell transplant (HSCT). GVHD is considered chronic when it occurs >100 days post-transplant, though aspects of cGVHD may manifest themselves prior to the 100 day point and overlap with elements of aGVHD. The disease has a cumulative incidence of 35-70% of transplanted patients, and has an annual incidence of approximately 3,000-5,000 and a prevalence of approximately 10,000 in the US. cGVHD is difficult to treat and is associated with worse outcomes compared to those without cGVHD. Current standard of care includes a variety of approaches including systemic corticosteroids often combined with calcineurin inhibitors, mTOR inhibitors, mycophenylate mofetil, or rituximab. Despite treatment, response rates are poor (40-50%) and cGVHD is associated with significant morbidity such as serious infection and impaired quality of life; the 5-year mortality is 30-50% (Blazar et al., Nature Reviews Immunology 12, 443-458, June 2012).

Human and animal models have demonstrated that aberrant B-lymphocyte signaling and survival is important in the pathogenesis of cGVHD. B-cell targeted drugs, including SYK inhibitors (fostamatinib – Sarantopoulos et al, Biology of Blood and Marrow Transplantation, 21(2015) S 11 -S 18) and BTK inhibitors (ibrutinib – Nakasone et al, Int. J. HematoL- 27 March 2015), have been shown to selectively reduce the function and frequency of aberrant GVHD B-cell populations ex vivo.

There remains a need for new methods, pharmaceutical compositions, and regimens for the treatment of GVHD, including aGVHD and cGVHD.

Example 2. Preparation of 6-(6-aminopyrazin-2-yl)-N-(4-(4-(oxetan-3-yl)piperazin-l- yl)phenyl)imid azo [ 1,2-a] pyrazin-8-amine (2)

2-Bis(tert-butoxycarbonyl)amino-6-bromopyrazine XIV: To a mixture of 6-bromopyrazin-2-amine (5 g, 28.7 mmol) and di-tert-butyl dicarbonate (25.09 g, 1 14.94 mmol) was added DCM (10 ml) followed by DMAP (0.351 g, 29 mmol). The reaction was heated to 55 °C for lh, cooled to RT, the reaction was partitioned between water and DCM, purified on silica gel and concentrated to provide of 2-bis(tert-butoxycarbonyl)amino-6-bromopyrazine XIV. LCMS-ESI⁺ (m/z): [M+H]⁺: 374.14. ^XH NMR (DMSO) δ: 8.84(d, 2H), 1.39 (s, 18H).

tert-Butyl (6-(6-(bis(tert-butoxycarbonyl)amino)pyrazin-2-yl)imidazo[l,2-a]pyrazin-8-yl)(4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)carbamate XVI – CHEMISTRY A route: tert-Butyl 4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl(6-(tributylstannyl)imidazo[l,2-a]pyrazin-8-yl)carbamate V (215 mg, 0.291 mmol), was combined with 2-bis(tert-butoxycarbonyl)amino-6-bromopyrazine XIV (217.58 mg, 0.581 mmol),

bis(triphenylphosphine)palladium(II) dichloride(30.61 mg, 0.044 mmol) and 1,4-dioxane (5ml). The reaction mixture was stirred in a microwave reactor at 120 °C for 30 min. The reaction mixture was quenched with saturated KF, extracted with EtOAc, purified on silica gel, eluted with EtOAc. The desired fractions were combined and concentrated to provide 100 mg (46% yield) of tert-butyl (6-(6-(bis(tert-butoxycarbonyl)amino)pyrazin-2-yl)imidazo[l,2-a]pyrazin-8-yl)(4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)carbamate XVI. LCMS-ESI⁺ (m/z): [M+H]⁺: 744.4. ^lH NMR (300 MHz d₆-DMSO) δ: 9.37 (s, 1H), 9.18 (s, 1H), 8.77 (s, 1H), 8.33 (d, 1H), 7.87 (d, 1H), 7.28-7.25 (d, 2H), 6.92-6.89 (d, 2H), 4.55-4.41 (m, 4H), 3.4 (m, lH), 3.14-3. 11 (m,4H), 2,37-2.34 (m, 4H), 1.37 (s, 18H), 1.3 (s, 9H).

tert-Butyl (6-(6-(bis(tert-butoxycarbonyl)amino)pyrazin-2-yl)imidazo[l,2-a]pyrazin-8-yl)(4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)carbamate XVI – CHEMISTRY B route: Step 1 : To a dry 250 mL round-bottomed flask was added 2-bis(tert-butoxycarbonyl)amino-6-bromopyrazine XIV (l .Og, l .Oequiv, 2.67mmol), KOAc (790mg, 8.02mmol, 3.0equiv), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(l ,3,2-dioxaborolane) (750mg, 2.94mmol, l . l equiv), Pd(dba) (171mg, 0.187mmol, 0.07equiv) and X-phos (128mg, 0.267mmol, O. lequiv) followed by 1,4-dioxane (25mL) and the solution was sonicated for 5 min and then purged with N₂ gas for 5 min. The flask with contents was then placed under N₂ atmosphere and heated at 1 10 °C for 90 min. Once full conversion to the pinacolboronate was achieved by LCMS, the reaction was removed from heat and allowed to cool to RT. Once cool, the reaction contents were filtered through Celite and the filter cake was washed 3 x 20 mL EtOAc. The resultant solution was then concentrated down to a deep red-orange

syrup providing N, N-BisBoc 6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazin-2-amine XV, which was used directly in the next step.

Step 2: The freshly formed N, N-BisBoc 6-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)pyrazin-2-amine XV (2.67 mmol based on 100% conversion, 2.0 equiv based on bromide) was dissolved in 20 Ml of 1,2-dimethoxy ethane and to that solution was added tert-butyl (6-bromoimidazo[l,2-a]pyrazin-8-yl)(4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)carbamate IV (707mg, 1.34mmol, l .Oequiv), Na2CC>3 (283mg, 2.67mmol, 2.0equiv), Pd(PPh₃)₄ (155mg, 0.134mmol, 0.1 equiv) and water (l OmL) and the solution was degassed for 5 min using N₂ gas. The reaction was then placed under N₂ atmosphere and heated at 110 °C for 90 min. LCMS showed complete consumption of the bromide starting material and the reaction was removed from heat and allowed to cool to RT. The reaction was diluted with 100 mL water and 100 mL 20% MeOH/DCM and the organic layer was recovered, extracted 1 x sat. NaHCCb, 1 x sat brine and then dried over Na2SC>4. The solution was then filtered and concentrated down to an orange-red solid. The sample was then slurried in warm MeOH, sonicated then filtered, washing 2 x 20 mL with cold MeOH and then the cream-colored solid was dried on hi-vacuum overnight to yield 905 mg of tert-butyl (6-(6-(bis(tert-butoxycarbonyl)amino)pyrazin-2-yl)imidazo[l,2-a]pyrazin-8-yl)(4-(4-(oxetan-3-yl)piperazin- 1 -yl)phenyl)carbamate XVI.

6-(6-Aminopyrazin-2-yl)-N-(4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)imidazo[l,2-a]pyrazin-8-amine (2): To a solution of tert-butyl (6-(6-(bis(tert-butoxycarbonyl)amino)pyrazin-2-yl)imidazo[l,2-a]pyrazin-8-yl)(4-(4-(oxetan-3-yl)piperazin-l -yl)phenyl)carbamate XVI (200 mg, 0.269 mmol) in DCM (2 ml) was added TFA (0.5 ml, 6.578 mmol). The reaction was stirred at rt for 16h, saturated sodium bicarbonate was added, extracted with EtOAC and purified on silica gel, eluted with 5%MeOH / EtOAc, 20%MeOH / EtOAc. The desired fractions were combined and concentrated to provide the title compound 2. LCMS-ESI⁺(m/z): [M+H]⁺: 444.2. ^lH NMR (300 MHz d₆-DMSO) δ: 9.5 (s, lH), 8.588 (s, IH), 8.47 (s, IH), 8. 12 (d, IH), 7.95-7.92 (d, 2H), 7.88 (s, IH), 7.62 (s, IH), 6.99-6.96 (d, 2H), 6.46 (s, 2H), 4.57-4.53 (m, 2H), 4.48-4.44 (m, 2H), 3.43 (m, IH), 3.15-3.12 (m, 4H), 2.41 -2.38 (m, 4H).

Example 2 – Alternate Synthesis

H₂S0₄, water 

Di-feri-butyl {6-[8-({4-[4-(oxetan-3-yl)piperazin-l-yl]phenyl}amino)imidazo[l,2-fl]pyrazin-6-yl]pyrazin-2-yl}imidodicarbonate:

To a 720 L reactor, was added di-fer/-butyl (6-bromopyrazin-2-yl)imidodicarbonate (18.5 kg, 1.41 equiv, 49 mol), bis(pinacolato)diboron (13.8 kg, 1.56 equiv, 54 mol), potassium propionate (11.9 kg, 3.02 equiv, 106 mol), and bis(di-fer/-butyl(4-dimethylaminophenyl) phosphine)dichloropalladium (1.07 kg, 0.0043 equiv, 1.5 mol), followed by degassed toluene (173 L). The mixture was degassed then heated at 65 °C until the reaction was deemed complete (0% tert-butyl 2-((6-bromopyrazin-2-yl)(tert-butoxycarbonyl)amino)-2-oxoacetate) by UPLC. Upon completion, the reaction was cooled to 23 °C. Once cooled, 6-bromo-N-(4-(4-(oxetan-3-yl)piperazin-l -yl)phenyl)imidazo[l ,2-a]pyrazin-8-amine (15.0 kg, 1.00 equiv, 35 mol) was added and the mixture was degassed. A degassed aqueous potassium carbonate solution prepared using water (54 L) and potassium carbonate (20.6 g, 4.26 equiv, 149 mol) was then added to the reaction mixture and the reactor contents was degassed. The reactor contents was heated at 65 °C until reaction was deemed complete (1% 6-bromo-N-(4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)imidazo[l,2-a]pyrazin-8-amine) by UPLC. Upon completion, the reaction was cooled to 24 °C.

The cooled mixture was concentrated and then diluted with dichloromethane (300 L), transferred to a 1900 L reactor and rinsed forward with dichloromethane (57 L). N-acetyl-L-cysteine (3.8 kg) was charged and the mixture was agitated for 15 h. Water (135 L) was then added and the mixture was filtered and rinsed forward with dichloromethane (68 L). The organic layer was recovered and washed with a brine solution prepared using water (68 L) and sodium chloride (7.5 kg).

The resultant organic layer was polish filtered then concentrated and fert-butyl methyl ether (89.9 kg) was slowly charged keeping the temperature at 31 °C. The contents was cooled to 0 °C and aged, then filtered and rinsed with tert-butyl methyl ether (32.7 kg) and dried at 40 °C to give 17.2 kg of di-tert-butyl {6-[8-({4-[4-(oxetan-3-yl)piperazin-l-yl]phenyl} amino)imidazo[l,2-a]pyrazin-6-yl]pyrazin-2-yl}imidodicarbonate.

LCMS-ESf (m/z): [M+H]⁺: 644.3. ^ΧΗ ΝΜΚ (400 MHz, CDC1₃) δ: 9.43 (s, 1H), 8.58 (s, 1H), 8.53 (s, 1H), 8.02 (s, 1H), 7.84 (m, 2H), 7.63 (d, 1H), 7.61 (d, 1H), 7.04 (m, 2H), 4.71 (m,4H), 3.59 (m, lH), 3.27 (m, 4H), 2.55 (m, 4H), 1.46 (s, 18H).

6-(6-Aminopyrazin-2-yl)-N-(4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)imidazo[l,2-a]pyrazin-8-amine succinate (Example 2):

To a slurry of di-tert-butyl {6-[8-({4-[4-(oxetan-3-yl)piperazin-l -yl]phenyl} amino)imidazo[l,2-a]pyrazin-6-yl]pyrazin-2-yl}imidodicarbonate (225 g, 0.35 mol, 1 mol eq.) in water (12 parts) was added a solution of sulfuric acid (3.1 parts, 6.99 mol, 20 mol eq.) in water (5 parts). The reaction was heated to ca. 40 °C and stirred at this temperature for ca. 4 h at which point the reaction is deemed complete. The reaction mixture was cooled to ca. 22 °C, acetone (3 parts) was charged and a solution of sodium carbonate (4.1 parts, 8.75 mol, 25.0 mol eq.) in water (15 parts) was added. The resulting slurry was filtered and the wet cake was washed with water in portions (4 x 1 parts), then with fert-butyl methyl ether (4 parts). The wet cake (Example 2 free base) was dried at ca. 60 °C. To the slurry of dry Example 2 free base in 2-propanol (2.3 parts) was added a solution of succinic acid (Based on the isolated Example 2 free base: 0.43 parts, 1.6 mol eq.) in 2-propanol (15 parts). The resulting slurry was heated to ca. 40 °C and stirred at this temperature for ca. 2 h and then cooled to ca. 22 °C, followed by a stir period of ca. 16 h. The slurry was filtered at ca. 22 °C and the wet cake was washed with 2-propanol (5 parts) and dried at ca. 60 °C to afford the product.

LCMS-ESI⁺ (m/z): [M+H]⁺: 620.65. ¾ NMR (400 MHz d₆-DMSO) δ: 12.2 (broad s, 1.5H), 9.58 (s, IH), 8.63 (s, IH), 8.50 (s, IH), 8.15 (s, IH), 7.95 (d, 2H), 7.90 (s, IH), 7.64 (s, IH), 7.00 (d, 2H), 6.50 (s, 2H), 4.52 (dd, 4H), 3.45 (m, IH), 3.19 (m, 4H), 2.40 (m, 10H).

REF

[1]. Di Paolo J, et al. FRI0049 Preclinical Characterization of GS-9876, A Novel, Oral SYK Inhibitor That Shows Efficacy in Multiple Established Rat Models of Collagen-Induced Arthritis.Annals of the Rheumatic Diseases 2016;75:443-444.

[2]. Clarke AS, et al. Effects of GS-9876, a novel spleen tyrosine kinase inhibitor, on platelet function and systemic hemostasis. Thromb Res. 2018 Oct;170:109-118.

[3]. Kivitz AJ, et al. GS-9876, a Novel, Highly Selective, SYK Inhibitor in Patients with Active Rheumatoid Arthritis: Safety, Tolerability and Efficacy Results of a Phase 2 Study [abstract]. Arthritis Rheumatol.2018; 70 (suppl 10).

/////////////LANRAPLENIB, GS-9876, SYK inhibitor

NC1=CN=CC(C2=CN3C(C(NC4=CC=C(N5CCN(C6COC6)CC5)C=C4)=N2)=NC=C3)=N1

Umifenovir

• Molecular FormulaC₂₂H₂₅BrN₂O₃S
• Average mass477.414 Da

Umifenovir^[2] (trade names Arbidol Russian: Арбидол, Chinese: 阿比朵尔) is an antiviral treatment for influenza infection used in Russia^[3] and China. The drug is manufactured by Pharmstandard (Russian: Фармстандарт). Although some Russian studies have shown it to be effective, it is not approved for use in other countries. It is not approved by FDA for the treatment or prevention of influenza.^[4] Chemically, umifenovir features an indole core, functionalized at all but one positions with different substituents. The drug is claimed to inhibit viral entry into target cells and stimulate the immune response. Interest in the drug has been renewed as a result of the SARS-CoV-2 outbreak.

Umifenovir is manufactured and made available as tablets, capsules and syrup.

Status

Testing of umifenovir’s efficacy has mainly occurred in China and Russia,^[5][6] and it is well known in these two countries.^[7] Some of the Russian tests showed the drug to be effective^[5] and a direct comparison with Tamiflu showed similar efficiency in vitro and in a clinical setting.^[8] In 2007, Arbidol (umifenovir) had the highest sales in Russia among all over-the-counter drugs.

Mode of action

Biochemistry

Umifenovir inhibits membrane fusion.^[3] Umifenovir prevents contact between the virus and target host cells. Fusion between the viral envelope (surrounding the viral capsid) and the cell membrane of the target cell is inhibited. This prevents viral entry to the target cell, and therefore protects it from infection.^[9]

Some evidence suggests that the drug’s actions are more effective at preventing infections from RNA viruses than infections from DNA viruses.^[10]

As well as specific antiviral action against both influenza A and influenza B viruses, umifenovir exhibits modulatory effects on the immune system. The drug stimulates a humoral immune response, induces interferon-production, and stimulates the phagocytic function of macrophages.^[11]

Clinical application

Umifenovir is used primarily as an antiviral treatments for influenza. The drug has also been investigated as a candidate drug for treatment of hepatitis C.^[12]

More recent studies indicate that umifenovir also has in vitro effectiveness at preventing entry of Ebolavirus Zaïre Kikwit, Tacaribe arenavirus and human herpes virus 8 in mammalian cell cultures, while confirming umifenovir’s suppressive effect in vitro on Hepatitis B and poliovirus infection of mammalian cells when introduced either in advance of viral infection or during infection.^[13][14]

Research

In February 2020, Li Lanjuan, an expert of the National Health Commission of China, proposed using Arbidol (umifenovir) together with darunavir as a potential treatment during the 2019–20 coronavirus pandemic.^[15] Chinese experts claim that preliminary tests had shown that arbidol and darunavir could inhibit replication of the virus.^[16][17] So far without additional effect if added on top of recombinant human interferon α2b spray.^[18]

Side effects

Side effects in children include sensitization to the drug. No known overdose cases have been reported and allergic reactions are limited to people with hypersensitivity. The LD₅₀ is more than 4 g/kg.^[19]

Criticism

In 2007, the Russian Academy of Medical Sciences stated that the effects of Arbidol (umifenovir) are not scientifically proven.^[20]

Russian media criticized lobbying attempts by Tatyana Golikova (then-Minister of Healthcare) to promote umifenovir,^[21] and the unproven claim that Arbidol can speed up recovery from flu or cold by 1.3-2.3 days.^[22] They also debunked claims that the efficacy of umifenovir is supported by peer-reviewed studies.^[23][24]

Clip

https://www.sciencedirect.com/science/article/pii/S0960894X1730687X

CLIP

1,2-Dimethyl-5-hydroxyindole-3-acetic acid ethyl ester (I) is acetylated with acetic anhydride affording the O-acyl derivative (II) , which is brominated to the corresponding dibromide compound (III) . The reaction of (III) with thiophenol in KOH yields (IV) , which is then submitted to a conventional Mannich condensation with formaldehyde and dimethylamine in acetic acid, giving the free base of arbidol (V), which is treated with aqueous hydrochloric acid .

References

External links

• “Мастерлек” Pharmaceuticals, Moscow, Russia. Patent number No. 2033157, Registry number No. 003610/01.
• (in Russian) Arbidol
• English published clinical studies and translations for Arbidol 1973–2016

Umifenovir

Clinical data
Trade names	Arbidol
Pregnancy category	C
Routes of administration	Oral (hard capsules, tablets)
ATC code	J05AX13 (WHO)
Legal status
Legal status	OTC RU
Pharmacokinetic data
Bioavailability	40%
Metabolism	Hepatic
Elimination half-life	17–21 hours
Excretion	40% excrete as unchanged umifenovir in feces (38.9%) and urine (0.12%)[1]
Identifiers
IUPAC name[show]
CAS Number	131707-25-0
PubChem CID	131411
DrugBank	DB13609
ChemSpider	116151
UNII	93M09WW4RU
ChEMBL	ChEMBL1214598
PDB ligand	75U (PDBe, RCSB PDB)
CompTox Dashboard (EPA)	DTXSID60895015
ECHA InfoCard	100.247.800
Chemical and physical data
Formula	C22H25BrN2O3S
Molar mass	477.41 g/mol g·mol−1
3D model (JSmol)	Interactive image
SMILES[hide] CCOC(=O)c1c(n(c2c1c(c(c(c2)Br)O)CN(C)C)C)CSc3ccccc3

Umifenovir is an indole-based, hydrophobic, dual-acting direct antiviral/host-targeting agent used for the treatment and prophylaxis of influenza and other respiratory infections.¹³ It has been in use in Russia for approximately 25 years and in China since 2006. Its invention is credited to a collaboration between Russian scientists from several research institutes 40-50 years ago, and reports of its chemical synthesis date back to 1993.¹³ Umifenovir’s ability to exert antiviral effects through multiple pathways has resulted in considerable investigation into its use for a variety of enveloped and non-enveloped RNA and DNA viruses, including Flavivirus,² Zika virus,³ foot-and-mouth disease,⁴ Lassa virus,⁶ Ebola virus,⁶ herpes simplex,⁸, hepatitis B and C viruses, chikungunya virus, reovirus, Hantaan virus, and coxsackie virus B5.^13,9 This dual activity may also confer additional protection against viral resistance, as the development of resistance to umifenovir does not appear to be significant.¹³

Umifenovir is currently being investigated as a potential treatment and prophylactic agent for COVID-19 caused by SARS-CoV2 infections in combination with both currently available and investigational HIV therapies.^1,16,17

Indication

Umifenovir is currently licensed in China and Russia for the prophylaxis and treatment of influenza and other respiratory viral infections.¹³ It has demonstrated activity against a number of viruses and has been investigated in the treatment of Flavivirus,² Zika virus,³ foot-and-mouth disease,⁴ Lassa virus,⁶ Ebola virus,⁶ and herpes simplex.⁸ In addition, it has shown in vitro activity against hepatitis B and C viruses, chikungunya virus, reovirus, Hantaan virus, and coxsackie virus B5.^13,9

Umifenovir is currently being investigated as a potential treatment and prophylactic agent for the prevention of COVID-19 caused by SARS-CoV-2 infections.^1,16

Pharmacodynamics

Umifenovir exerts its antiviral effects via both direct-acting virucidal activity and by inhibiting one (or several) stage(s) of the viral life cycle.¹³ Its broad-spectrum of activity covers both enveloped and non-enveloped RNA and DNA viruses. It is relatively well-tolerated and possesses a large therapeutic window – weight-based doses up to 100-fold greater than those used in humans failed to produce any pathological changes in test animals.¹³

Umifenovir does not appear to result in significant viral resistance. Instances of umifenovir-resistant influenza virus demonstrated a single mutation in the HA2 subunit of influenza hemagglutinin, suggesting resistance is conferred by prevention of umifenovir’s activity related to membrane fusion. The mechanism through which other viruses may become resistant to umifenovir requires further study.¹³

Mechanism of action

Umifenovir is considered both a direct-acting antiviral (DAA) due to direct virucidal effects and a host-targeting agent (HTA) due to effects on one or multiple stages of viral life cycle (e.g. attachment, internalization), and its broad-spectrum antiviral activity is thought to be due to this dual activity.¹³ It is a hydrophobic molecule capable of forming aromatic stacking interactions with certain amino acid residues (e.g. tyrosine, tryptophan), which contributes to its ability to directly act against viruses. Antiviral activity may also be due to interactions with aromatic residues within the viral glycoproteins involved in fusion and cellular recognition,^5,7 with the plasma membrane to interfere with clathrin-mediated exocytosis and intracellular trafficking,¹⁰ or directly with the viral lipid envelope itself (in enveloped viruses).^13,12 Interactions at the plasma membrane may also serve to stabilize it and prevent viral entry (e.g. stabilizing influenza hemagglutinin inhibits the fusion step necessary for viral entry).¹³

Due to umifenovir’s ability to interact with both viral proteins and lipids, it may also interfere with later stages of the viral life cycle. Some virus families, such as Flaviviridae, replicate in a subcellular compartment called the membranous web – this web requires lipid-protein interactions that may be hindered by umifenovir. Similarly, viral assembly of hepatitis C viruses is contingent upon the assembly of lipoproteins, presenting another potential target.¹³

Absorption

Umifenovir is rapidly absorbed following oral administration, with an estimated T_max between 0.65-1.8 hours.^14,15,13 The C_max has been estimated as 415 – 467 ng/mL and appears to increase linearly with dose,^14,15 and the AUC_0-inf following oral administration has been estimated to be approximately 2200 ng/mL/h.^14,15

Volume of distribution

Data regarding the volume of distribution of umifenovir are currently unavailable.

Protein binding

Data regarding protein-binding of umifenovir are currently unavailable.

Metabolism

Umifenovir is highly metabolized in the body, primarily in hepatic and intestinal microsomess, with approximately 33 metabolites having been observed in human plasma, urine, and feces.¹⁴ The principal phase I metabolic pathways include sulfoxidation, N-demethylation, and hydroxylation, followed by phase II sulfate and glucuronide conjugation. In the urine, the major metabolites were sulfate and glucuronide conjugates, while the major species in the feces was unchanged parent drug (~40%) and the M10 metabolite (~3.0%). In the plasma, the principal metabolites are M6-1, M5, and M8 – of these, M6-1 appears of most importance given its high plasma exposure and long elimination half-life (~25h), making it a potentially important player in the safety and efficacy of umifenovir.¹⁴

Enzymes involved in the metabolism of umifenovir include members of the cytochrome P450 family (primarily CYP3A4), flavin-containing monooxygenase (FMO) family, and UDP-glucuronosyltransferase (UGT) family (specifically UGT1A9 and UGT2B7).^14,11

1. Lu H: Drug treatment options for the 2019-new coronavirus (2019-nCoV). Biosci Trends. 2020 Jan 28. doi: 10.5582/bst.2020.01020. [PubMed:31996494]
2. Haviernik J, Stefanik M, Fojtikova M, Kali S, Tordo N, Rudolf I, Hubalek Z, Eyer L, Ruzek D: Arbidol (Umifenovir): A Broad-Spectrum Antiviral Drug That Inhibits Medically Important Arthropod-Borne Flaviviruses. Viruses. 2018 Apr 10;10(4). pii: v10040184. doi: 10.3390/v10040184. [PubMed:29642580]
3. Fink SL, Vojtech L, Wagoner J, Slivinski NSJ, Jackson KJ, Wang R, Khadka S, Luthra P, Basler CF, Polyak SJ: The Antiviral Drug Arbidol Inhibits Zika Virus. Sci Rep. 2018 Jun 12;8(1):8989. doi: 10.1038/s41598-018-27224-4. [PubMed:29895962]
4. Herod MR, Adeyemi OO, Ward J, Bentley K, Harris M, Stonehouse NJ, Polyak SJ: The broad-spectrum antiviral drug arbidol inhibits foot-and-mouth disease virus genome replication. J Gen Virol. 2019 Sep;100(9):1293-1302. doi: 10.1099/jgv.0.001283. Epub 2019 Jun 4. [PubMed:31162013]
5. Kadam RU, Wilson IA: Structural basis of influenza virus fusion inhibition by the antiviral drug Arbidol. Proc Natl Acad Sci U S A. 2017 Jan 10;114(2):206-214. doi: 10.1073/pnas.1617020114. Epub 2016 Dec 21. [PubMed:28003465]
6. Hulseberg CE, Feneant L, Szymanska-de Wijs KM, Kessler NP, Nelson EA, Shoemaker CJ, Schmaljohn CS, Polyak SJ, White JM: Arbidol and Other Low-Molecular-Weight Drugs That Inhibit Lassa and Ebola Viruses. J Virol. 2019 Apr 3;93(8). pii: JVI.02185-18. doi: 10.1128/JVI.02185-18. Print 2019 Apr 15. [PubMed:30700611]
7. Zeng LY, Yang J, Liu S: Investigational hemagglutinin-targeted influenza virus inhibitors. Expert Opin Investig Drugs. 2017 Jan;26(1):63-73. doi: 10.1080/13543784.2017.1269170. Epub 2016 Dec 14. [PubMed:27918208]
8. Li MK, Liu YY, Wei F, Shen MX, Zhong Y, Li S, Chen LJ, Ma N, Liu BY, Mao YD, Li N, Hou W, Xiong HR, Yang ZQ: Antiviral activity of arbidol hydrochloride against herpes simplex virus I in vitro and in vivo. Int J Antimicrob Agents. 2018 Jan;51(1):98-106. doi: 10.1016/j.ijantimicag.2017.09.001. Epub 2017 Sep 7. [PubMed:28890393]
9. Pecheur EI, Borisevich V, Halfmann P, Morrey JD, Smee DF, Prichard M, Mire CE, Kawaoka Y, Geisbert TW, Polyak SJ: The Synthetic Antiviral Drug Arbidol Inhibits Globally Prevalent Pathogenic Viruses. J Virol. 2016 Jan 6;90(6):3086-92. doi: 10.1128/JVI.02077-15. [PubMed:26739045]
10. Blaising J, Levy PL, Polyak SJ, Stanifer M, Boulant S, Pecheur EI: Arbidol inhibits viral entry by interfering with clathrin-dependent trafficking. Antiviral Res. 2013 Oct;100(1):215-9. doi: 10.1016/j.antiviral.2013.08.008. Epub 2013 Aug 25. [PubMed:23981392]
11. Song JH, Fang ZZ, Zhu LL, Cao YF, Hu CM, Ge GB, Zhao DW: Glucuronidation of the broad-spectrum antiviral drug arbidol by UGT isoforms. J Pharm Pharmacol. 2013 Apr;65(4):521-7. doi: 10.1111/jphp.12014. Epub 2012 Dec 24. [PubMed:23488780]
12. Teissier E, Zandomeneghi G, Loquet A, Lavillette D, Lavergne JP, Montserret R, Cosset FL, Bockmann A, Meier BH, Penin F, Pecheur EI: Mechanism of inhibition of enveloped virus membrane fusion by the antiviral drug arbidol. PLoS One. 2011 Jan 25;6(1):e15874. doi: 10.1371/journal.pone.0015874. [PubMed:21283579]
13. Blaising J, Polyak SJ, Pecheur EI: Arbidol as a broad-spectrum antiviral: an update. Antiviral Res. 2014 Jul;107:84-94. doi: 10.1016/j.antiviral.2014.04.006. Epub 2014 Apr 24. [PubMed:24769245]
14. Deng P, Zhong D, Yu K, Zhang Y, Wang T, Chen X: Pharmacokinetics, metabolism, and excretion of the antiviral drug arbidol in humans. Antimicrob Agents Chemother. 2013 Apr;57(4):1743-55. doi: 10.1128/AAC.02282-12. Epub 2013 Jan 28. [PubMed:23357765]
15. Liu MY, Wang S, Yao WF, Wu HZ, Meng SN, Wei MJ: Pharmacokinetic properties and bioequivalence of two formulations of arbidol: an open-label, single-dose, randomized-sequence, two-period crossover study in healthy Chinese male volunteers. Clin Ther. 2009 Apr;31(4):784-92. doi: 10.1016/j.clinthera.2009.04.016. [PubMed:19446151]
16. Wang Z, Chen X, Lu Y, Chen F, Zhang W: Clinical characteristics and therapeutic procedure for four cases with 2019 novel coronavirus pneumonia receiving combined Chinese and Western medicine treatment. Biosci Trends. 2020 Feb 9. doi: 10.5582/bst.2020.01030. [PubMed:32037389]
17. Nature Biotechnology: Coronavirus puts drug repurposing on the fast track [Link]

/////////////////Arbidol, umifenovir, covid 19, corona virus, Арбидол , 阿比朵尔 , 

CCOC(=O)C1=C(CSC2=CC=CC=C2)N(C)C2=CC(Br)=C(O)C(CN(C)C)=C12

https://eurekalert.org/pub_releases/2020-02/nuos-edm022620.php

Hydroxychloroquine (HCQ), sold under the brand name Plaquenil among others, is a medication used for the prevention and treatment of certain types of malaria.^[2] Specifically it is used for chloroquine-sensitive malaria.^[3] Other uses include treatment of rheumatoid arthritis, lupus, and porphyria cutanea tarda.^[2] It is taken by mouth.^[2] It is also being used as an experimental treatment for coronavirus disease 2019 (COVID-19).^[4]

Common side effects include vomiting, headache, changes in vision and muscle weakness.^[2] Severe side effects may include allergic reactions.^[2] Although all risk cannot be excluded it remains a treatment for rheumatic disease during pregnancy.^[5] Hydroxychloroquine is in the antimalarial and 4-aminoquinoline families of medication.^[2]

Hydroxychloroquine was approved for medical use in the United States in 1955.^[2] It is on the World Health Organization’s List of Essential Medicines, the safest and most effective medicines needed in a health system.^[6] The wholesale cost in the developing world is about US$4.65 per month as of 2015, when used for rheumatoid arthritis or lupus.^[7] In the United States the wholesale cost of a month of treatment is about US$25 as of 2020.^[8] In the United Kingdom this dose costs the NHS about £ 5.15.^[9] In 2017, it was the 128th most prescribed medication in the United States with more than five million prescriptions.^[10]

Medical use

Hydroxychloroquine treats malaria, systemic lupus erythematosus, rheumatic disorders like rheumatoid arthritis, porphyria cutanea tarda, and Q fever.^[2]

In 2014, its efficacy to treat Sjögren syndrome was questioned in a double-blind study involving 120 patients over a 48-week period.^[11]

Hydroxychloroquine is widely used in the treatment of post-Lyme arthritis. It may have both an anti-spirochaete activity and an anti-inflammatory activity, similar to the treatment of rheumatoid arthritis.^[12]

Contraindications

The drug label advises that hydroxychloroquine should not be prescribed to individuals with known hypersensitivity to 4-Aminoquinoline compounds.^[13] There are a range of other contraindications^[14] [15] and caution is required if patients have certain heart conditions, diabetes, psoriasis etc.

Side effects[

The most common adverse effects are a mild nausea and occasional stomach cramps with mild diarrhea. The most serious adverse effects affect the eye, with dose-related retinopathy as a concern even after hydroxychloroquine use is discontinued.^[2] For short-term treatment of acute malaria, adverse effects can include abdominal cramps, diarrhea, heart problems, reduced appetite, headache, nausea and vomiting.^[2]

For prolonged treatment of lupus or rheumatoid arthritis, adverse effects include the acute symptoms, plus altered eye pigmentation, acne, anemia, bleaching of hair, blisters in mouth and eyes, blood disorders, convulsions, vision difficulties, diminished reflexes, emotional changes, excessive coloring of the skin, hearing loss, hives, itching, liver problems or liver failure, loss of hair, muscle paralysis, weakness or atrophy, nightmares, psoriasis, reading difficulties, tinnitus, skin inflammation and scaling, skin rash, vertigo, weight loss, and occasionally urinary incontinence.^[2] Hydroxychloroquine can worsen existing cases of both psoriasis and porphyria.^[2]

Children may be especially vulnerable to developing adverse effects from hydroxychloroquine.^[2]

Eyes

One of the most serious side effects is retinopathy (generally with chronic use).^[2][16] People taking 400 mg of hydroxychloroquine or less per day generally have a negligible risk of macular toxicity, whereas the risk begins to go up when a person takes the medication over 5 years or has a cumulative dose of more than 1000 grams. The daily safe maximum dose for eye toxicity can be computed from one’s height and weight using this calculator. Cumulative doses can also be calculated from this calculator. Macular toxicity is related to the total cumulative dose rather than the daily dose. Regular eye screening, even in the absence of visual symptoms, is recommended to begin when either of these risk factors occurs.^[17]

Toxicity from hydroxychloroquine may be seen in two distinct areas of the eye: the cornea and the macula. The cornea may become affected (relatively commonly) by an innocuous cornea verticillata or vortex keratopathy and is characterized by whorl-like corneal epithelial deposits. These changes bear no relationship to dosage and are usually reversible on cessation of hydroxychloroquine.

The macular changes are potentially serious. Advanced retinopathy is characterized by reduction of visual acuity and a “bull’s eye” macular lesion which is absent in early involvement.

Overdose

Due to rapid absorption, symptoms of overdose can occur within a half an hour after ingestion. Overdose symptoms include convulsions, drowsiness, headache, heart problems or heart failure, difficulty breathing and vision problems.

Hydroxychloroquine overdoses are rarely reported, with 7 previous cases found in the English medical literature. In one such case, a 16-year-old girl who had ingested a handful of hydroxychloroquine 200mg presented with tachycardia (heart rate 110 beats/min), hypotension (systolic blood pressure 63 mm Hg), central nervous system depression, conduction defects (ORS = 0.14 msec), and hypokalemia (K = 2.1 meq/L). Treatment consisted of fluid boluses and dopamine, oxygen, and potassium supplementation. The presence of hydroxychloroquine was confirmed through toxicologic tests. The patient’s hypotension resolved within 4.5 hours, serum potassium stabilized in 24 hours, and tachycardia gradually decreased over 3 days.^[18]

Interactions

The drug transfers into breast milk and should be used with care by pregnant or nursing mothers.^{[citation needed]}

Care should be taken if combined with medication altering liver function as well as aurothioglucose (Solganal), cimetidine (Tagamet) or digoxin (Lanoxin). HCQ can increase plasma concentrations of penicillamine which may contribute to the development of severe side effects. It enhances hypoglycemic effects of insulin and oral hypoglycemic agents. Dose altering is recommended to prevent profound hypoglycemia. Antacids may decrease the absorption of HCQ. Both neostigmine and pyridostigmine antagonize the action of hydroxychloroquine.^[19]

While there may be a link between hydroxychloroquine and hemolytic anemia in those with glucose-6-phosphate dehydrogenase deficiency, this risk may be low in those of African descent.^[20]

Specifically, the FDA drug label for hydroxychloroquine lists the following drug interactions ^[13]:

• Digoxin (wherein it may result in increased serum digoxin levels)
• Insulin or antidiabetic drugs (wherein it may enhance the effects of a hypoglycemic treatment)
• Drugs that prolong QT interval and other arrhythmogenic drugs (as Hydroxychloroquine prolongs the QT interval and may increase the risk of inducing ventricular arrhythmias if used concurrently)
• Mefloquine and other drugs known to lower the convulsive threshold (co-administration with other antimalarials known to lower the convulsion threshold may increase risk of convulsions)
• Antiepileptics (concurrent use may impair the antiepileptic activity)
• Methotrexate (combined use is unstudied and may increase the frequency of side effects)
• Cyclosporin (wherein an increased plasma cylcosporin level was reported when used together).

Pharmacology[

Pharmacokinetics

Hydroxychloroquine has similar pharmacokinetics to chloroquine, with rapid gastrointestinal absorption and elimination by the kidneys. Cytochrome P450 enzymes (CYP2D6, 2C8, 3A4 and 3A5) metabolize hydroxychloroquine to N-desethylhydroxychloroquine.^[21]

Pharmacodynamics

Antimalarials are lipophilic weak bases and easily pass plasma membranes. The free base form accumulates in lysosomes (acidic cytoplasmic vesicles) and is then protonated,^[22] resulting in concentrations within lysosomes up to 1000 times higher than in culture media. This increases the pH of the lysosome from 4 to 6.^[23] Alteration in pH causes inhibition of lysosomal acidic proteases causing a diminished proteolysis effect.^[24] Higher pH within lysosomes causes decreased intracellular processing, glycosylation and secretion of proteins with many immunologic and nonimmunologic consequences.^[25] These effects are believed to be the cause of a decreased immune cell functioning such as chemotaxis, phagocytosis and superoxide production by neutrophils.^[26] HCQ is a weak diprotic base that can pass through the lipid cell membrane and preferentially concentrate in acidic cytoplasmic vesicles. The higher pH of these vesicles in macrophages or other antigen-presenting cells limits the association of autoantigenic (any) peptides with class II MHC molecules in the compartment for peptide loading and/or the subsequent processing and transport of the peptide-MHC complex to the cell membrane.^[27]

Mechanism of action

Hydroxychloroquine increases^[28] lysosomal pH in antigen-presenting cells. In inflammatory conditions, it blocks toll-like receptors on plasmacytoid dendritic cells (PDCs).^{[citation needed]} Hydroxychloroquine, by decreasing TLR signaling, reduces the activation of dendritic cells and the inflammatory process. Toll-like receptor 9 (TLR 9) recognizes DNA-containing immune complexes and leads to the production of interferon and causes the dendritic cells to mature and present antigen to T cells, therefore reducing anti-DNA auto-inflammatory process.

In 2003, a novel mechanism was described wherein hydroxychloroquine inhibits stimulation of the toll-like receptor (TLR) 9 family receptors. TLRs are cellular receptors for microbial products that induce inflammatory responses through activation of the innate immune system.^[29]

As with other quinoline antimalarial drugs, the mechanism of action of quinine has not been fully resolved. The most accepted model is based on hydrochloroquinine and involves the inhibition of hemozoin biocrystallization, which facilitates the aggregation of cytotoxic heme. Free cytotoxic heme accumulates in the parasites, causing their deaths.^{[citation needed]}

Brand names

It is frequently sold as a sulfate salt known as hydroxychloroquine sulfate.^[2] 200 mg of the sulfate salt is equal to 155 mg of the base.^[2]

Brand names of hydroxychloroquine include Plaquenil, Hydroquin, Axemal (in India), Dolquine, Quensyl, Quinoric.^[30]

Research

COVID-19

Hydroxychloroquine and chloroquine have been recommended by Chinese and South Korean health authorities for the experimental treatment of COVID-19.^[31][32] In vitro studies in cell cultures demonstrated that hydroxychloroquine was more potent than chloroquine against SARS-CoV-2.^[33]

On 17 March 2020, the AIFA Scientific Technical Commission of the Italian Medicines Agency expressed a favorable opinion on including the off-label use of chloroquine and hydroxychloroquine for the treatment of SARS-CoV-2 infection.^[34]

clip

clip

https://d-nb.info/1166863441/34

white solid (0.263 g, 78%). 1H NMR
(600 MHz, CDCl3
) δ 8.48 (d, J = 5.4 Hz, 1H), 7.93 (d, J = 5.4 Hz, 1H), 7.70 (d, J = 9.2 Hz, 1H), 7.34 (dd, J = 8.8, 7.3 Hz, 1H), 6.39 (d, J = 5.4 Hz, 1H), 4.96 (d, J = 7.5 Hz, 1H), 3.70 (sx,J = 6.8 Hz, 1H), 3.55 (m, 2H), 2.57 (m, 5H), 2.49 (m, 2H),
1.74–1.62 (m, 1H), 1.65–1.53 (m, 3H), 1.31 (d, J = 6.9 Hz, 3H),
1.24 (d, J = 7.2 Hz, 2H);

13C NMR (125 MHz, CDCl3) δ 152.2,
149.5, 149.2, 135.0, 129.0, 125.4, 121.2, 117.4, 99.4, 58.6, 54.9,
53.18, 48.5, 47.9, 34.5, 24.1, 20.6, 11.9. Spectra were obtained
in accordance with those previously reported [38,39].

38. Cornish, C. A.; Warren, S. J. Chem. Soc., Perkin Trans. 1 1985,
2585–2598. doi:10.1039/P19850002585
39. Münstedt, R.; Wannagat, U.; Wrobel, D. J. Organomet. Chem. 1984,
264, 135–148. doi:10.1016/0022-328X(84)85139-6

References

External links

• “Hydroxychloroquine”. Drug Information Portal. U.S. National Library of Medicine.

Hydroxychloroquine

Hydroxychloroquine freebase molecule
Clinical data
Trade names	Plaquenil, others
Other names	Hydroxychloroquine sulfate
AHFS/Drugs.com	Monograph
MedlinePlus	a601240
License data	US DailyMed: Hydroxychloroquine
Pregnancy category	AU: D [1] US: N (Not classified yet) [1]
Routes of administration	By mouth (tablets)
ATC code	P01BA02 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) UK: POM (Prescription only) US: ℞-only In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability	Variable (74% on average); Tmax = 2–4.5 hours
Protein binding	45%
Metabolism	Liver
Elimination half-life	32–50 days
Excretion	Mostly Kidney (23–25% as unchanged drug), also biliary (<10%)
Identifiers
IUPAC name[show]
CAS Number	118-42-3
PubChem CID	3652
IUPHAR/BPS	7198
DrugBank	DB01611
ChemSpider	3526
UNII	4QWG6N8QKH
KEGG	D08050  C07043
ChEBI	CHEBI:5801
ChEMBL	ChEMBL1535
CompTox Dashboard (EPA)	DTXSID8023135
ECHA InfoCard	100.003.864
Chemical and physical data
Formula	C18H26ClN3O
Molar mass	335.872 g/mol g·mol−1
3D model (JSmol)	Interactive image
SMILES[hide] Clc1cc2nccc(c2cc1)NC(C)CCCN(CC)CCO

///////////Hydroxychloroquine, Hydroxy chloroquine, HCQ, ヒドロキシクロロキン , covid 19, coronavirus, antimalarial, гидроксихлорохин , هيدروكسيكلوروكين , 羟氯喹 , Oxychlorochin, Plaquenil , Plaquenil®, 

Nitazoxanide

Nitazoxanide is a broad-spectrum antiparasitic and broad-spectrum antiviral drug that is used in medicine for the treatment of various helminthic, protozoal, and viral infections.^[4][5][6] It is indicated for the treatment of infection by Cryptosporidium parvum and Giardia lamblia in immunocompetent individuals and has been repurposed for the treatment of influenza.^[1][6] Nitazoxanide has also been shown to have in vitro antiparasitic activity and clinical treatment efficacy for infections caused by other protozoa and helminths;^[4][7] emerging evidence suggests that it possesses efficacy in treating a number of viral infections as well.^[6]

Chemically, nitazoxanide is the prototype member of the thiazolides, a class of drugs which are synthetic nitrothiazolyl-salicylamide derivatives with antiparasitic and antiviral activity.^[4][6][8] Tizoxanide, an active metabolite of nitazoxanide in humans, is also an antiparasitic drug of the thiazolide class.^[4][9]

Uses

Nitazoxanide is an effective first-line treatment for infection by Blastocystis species^[10][11] and is indicated for the treatment of infection by Cryptosporidium parvum or Giardia lamblia in immunocompetent adults and children.^[1] It is also an effective treatment option for infections caused by other protozoa and helminths (e.g., Entamoeba histolytica,^[12] Hymenolepis nana,^[13] Ascaris lumbricoides,^[14] and Cyclospora cayetanensis^[15]).^[7]

As of September 2015, it is in phase 3 clinical trials for the treatment influenza due to its inhibitory effect on a broad range of influenza virus subtypes and efficacy against influenza viruses that are resistant to neuraminidase inhibitors like oseltamivir.^[6][16] Nitazoxanide is also being researched as a potential treatment for chronic hepatitis B, chronic hepatitis C, rotavirus and norovirus gastroenteritis.^[6]

Chronic hepatitis B

Nitazoxanide alone has shown preliminary evidence of efficacy in the treatment of chronic hepatitis B over a one-year course of therapy.^[17] Nitazoxanide 500 mg twice daily resulted in a decrease in serum HBV DNA in all of 4 HBeAg-positive patients, with undetectable HBV DNA in 2 of 4 patients, loss of HBeAg in 3 patients, and loss of HBsAg in one patient. Seven of 8 HBeAg-negative patients treated with nitazoxanide 500 mg twice daily had undetectable HBV DNA and 2 had loss of HBsAg. Additionally, nitazoxanide monotherapy in one case and nitazoxanide plus adefovir in another case resulted in undetectable HBV DNA, loss of HBeAg and loss of HBsAg.^[18] These preliminary studies showed a higher rate of HBsAg loss than any currently licensed therapy for chronic hepatitis B. The similar mechanism of action of interferon and nitazoxanide suggest that stand-alone nitazoxanide therapy or nitazoxanide in concert with nucleos(t)ide analogs have the potential to increase loss of HBsAg, which is the ultimate end-point of therapy. A formal phase Ⅱ study is being planned for 2009.^[19]

Chronic hepatitis C

Romark initially decided to focus on the possibility of treating chronic hepatitis C with nitazoxanide.^[20] The drug garnered interest from the hepatology community after three phase II clinical trials involving the treatment of hepatitis C with nitazoxanide produced positive results for treatment efficacy and similar tolerability to placebo without any signs of toxicity.^[20] A meta-analysis from 2014 concluded that the previous held trials were of low-quality and with held with a risk of bias. The authors concluded that more randomized trials with low risk of bias are needed to give any determine if Nitazoxanide can be used as an effective treatment for chronic hepatitis C patients.^[21]

Clinical trials

Nitazoxanide has gone through Phase II clinical trials for the treatment of hepatitis C, in combination with peginterferon alfa-2a and ribavirin.^[22][23]Romark Laboratories has announced encouraging results from international Phase I and II clinical trials evaluating a controlled release version of nitazoxanide in the treatment of chronic hepatitis C virus infection. The company used 675 mg and 1,350 mg twice daily doses of controlled release nitazoxanide showed favorable safety and tolerability throughout the course of the study, with mild to moderate adverse events. Primarily GI-related adverse events were reported.

A randomised double-blind placebo-controlled study published in 2006, with a group of 38 young children (Lancet, vol 368, page 124-129)^[24] concluded that a 3-day course of nitazoxanide significantly reduced the duration of rotavirus disease in hospitalized pediatric patients. Dose given was “7.5 mg/kg twice daily” and the time of resolution was “31 hours for those given nitazoxanide compared with 75 hours for those in the placebo group.” Rotavirus is the most common infectious agent associated with diarrhea in the pediatric age group worldwide.

Teran et al.. conducted a study at the Pediatric Center Albina Patinö, a reference hospital in the city of Cochabamba, Bolivia, from August 2007 to February 2008. The study compared nitazoxanide and probiotics in the treatment of acute rotavirus diarrhea. They found Small differences in favor of nitazoxanide in comparison with probiotics and concluded that nitazoxanide is an important treatment option for rotavirus diarrhea.^[17]

Lateef et al.. conducted a study in India that evaluated the effectiveness of nitazoxanide in the treatment of beef tapeworm (Taenia saginata) infection. They concluded that nitazoxanide is a safe, effective, inexpensive, and well-tolerated drug for the treatment of niclosamide- and praziquantel-resistant beef tapeworm (Taenia saginata) infection.^[18]

A retrospective review of charts of patients treated with nitazoxanide for trichomoniasis by Michael Dan and Jack D. Sobel demonstrated negative result. They reported three case studies; two of which with metronidazole-resistant infections. In Case 3, they reported the patient to be cured with high divided dose tinidazole therapy. They used a high dosage of the drug (total dose, 14–56 g) than the recommended standard dosage (total dose, 3 g) and observed a significant adverse reaction (poorly tolerated nausea) only with the very high dose (total dose, 56 g). While confirming the safety of the drug, they showed nitazoxanide is ineffective for the treatment of trichomoniasis.^[25]

Contraindications

Nitazoxanide is contraindicated only in individuals who have experienced a hypersensitivity reaction to nitazoxanide or the inactive ingredients of a nitazoxanide formulation.^[1]

Adverse effects

The side effects of nitazoxanide do not significantly differ from a placebo treatment for giardiasis;^[1] these symptoms include stomach pain, headache, upset stomach, vomiting, discolored urine, excessive urinating, skin rash, itching, fever, flu syndrome, and others.^[1][26] Nitazoxanide does not appear to cause any significant adverse effects when taken by healthy adults.^[1][2]

Overdose

Information on nitazoxanide overdose is limited. Oral doses of 4 grams in healthy adults do not appear to cause any significant adverse effects.^[1][2] In various animals, the oral LD₅₀ is higher than 10 g/kg.^[1]

Interactions

Due to the exceptionally high plasma protein binding (>99.9%) of nitazoxanide’s metabolite, tizoxanide, the concurrent use of nitazoxanide with other highly plasma protein-bound drugs with narrow therapeutic indices (e.g., warfarin) increases the risk of drug toxicity.^[1] In vitro evidence suggests that nitazoxanide does not affect the CYP450 system.^[1]

Pharmacology

Pharmacodynamics

The anti-protozoal activity of nitazoxanide is believed to be due to interference with the pyruvate:ferredoxin oxidoreductase (PFOR) enzyme-dependent electron transfer reaction which is essential to anaerobic energy metabolism.^[1][8] PFOR inhibition may also contribute to its activity against anaerobic bacteria.^[27]

It has also been shown to have activity against influenza A virus in vitro.^[28] The mechanism appears to be by selectively blocking the maturation of the viral hemagglutinin at a stage preceding resistance to endoglycosidase H digestion. This impairs hemagglutinin intracellular trafficking and insertion of the protein into the host plasma membrane.

Nitazoxanide modulates a variety of other pathways in vitro, including glutathione-S-transferase and glutamate-gated chloride ion channels in nematodes, respiration and other pathways in bacteria and cancer cells, and viral and host transcriptional factors.^[27]

Pharmacokinetics

Following oral administration, nitazoxanide is rapidly hydrolyzed to the pharmacologically active metabolite, tizoxanide, which is 99% protein bound.^[1][9] Tizoxanide is then glucuronide conjugated into the active metabolite, tizoxanide glucuronide.^[1] Peak plasma concentrations of the metabolites tizoxanide and tizoxanide glucuronide are observed 1–4 hours after oral administration of nitazoxanide, whereas nitazoxanide itself is not detected in blood plasma.^[1]

Roughly ​²⁄₃ of an oral dose of nitazoxanide is excreted as its metabolites in feces, while the remainder of the dose excreted in urine.^[1] Tizoxanide is excreted in the urine, bile and feces.^[1] Tizoxanide glucuronide is excreted in urine and bile.^[1]

Chemistry

History

Nitazoxanide is the prototype member of the thiazolides, which is a drug class of structurally-related broad-spectrum antiparasitic compounds.^[4] Nitazoxanide is a light yellow crystalline powder. It is poorly soluble in ethanol and practically insoluble in water.

Nitazoxanide was originally discovered in the 1980s by Jean-François Rossignol at the Pasteur Institute. Initial studies demonstrated activity versus tapeworms. In vitro studies demonstrated much broader activity. Dr. Rossignol co-founded Romark Laboratories, with the goal of bringing nitazoxanide to market as an anti-parasitic drug. Initial studies in the USA were conducted in collaboration with Unimed Pharmaceuticals, Inc. (Marietta, GA) and focused on development of the drug for treatment of cryptosporidiosis in AIDS. Controlled trials began shortly after the advent of effective anti-retroviral therapies. The trials were abandoned due to poor enrollment and the FDA rejected an application based on uncontrolled studies.

Subsequently, Romark launched a series of controlled trials. A placebo-controlled study of nitazoxanide in cryptosporidiosis demonstrated significant clinical improvement in adults and children with mild illness. Among malnourished children in Zambia with chronic cryptosporidiosis, a three-day course of therapy led to clinical and parasitologic improvement and improved survival. In Zambia and in a study conducted in Mexico, nitazoxanide was not successful in the treatment of cryptosporidiosis in advanced infection with human immunodeficiency virus at the doses used. However, it was effective in patients with higher CD4 counts. In treatment of giardiasis, nitazoxanide was superior to placebo and comparable to metronidazole. Nitazoxanide was successful in the treatment of metronidazole-resistant giardiasis. Studies have suggested efficacy in the treatment of cyclosporiasis, isosporiasis, and amebiasis.^[29] Recent studies have also found it to be effective against beef tapeworm(Taenia saginata).^[30]

Research

Nitazoxanide is also under investigation for the treatment of COVID-19.^[31]

Pharmaceutical products

Dosage forms

Nitazoxanide is currently available in two oral dosage forms: a tablet (500 mg) and an oral suspension (100 mg per 5 ml when reconstituted).^[1]

An extended release tablet (675 mg) has been used in clinical trials for chronic hepatitis C; however, this form is not currently marketed and available for prescription.^[20]

Brand names

Nitazoxanide is sold under the brand names Adonid, Alinia, Allpar, Annita, Celectan, Colufase, Daxon, Dexidex, Diatazox, Kidonax, Mitafar, Nanazoxid, Parazoxanide, Netazox, Niazid, Nitamax, Nitax, Nitaxide, Nitaz, Nizonide, NT-TOX, Pacovanton, Paramix, Toza, and Zox.

SYN

https://www.sciencedirect.com/science/article/pii/S0960894X11002848

CLIP

CLIP

PATENT

https://patents.google.com/patent/CN105175352A/zh

References

External links

• “Nitazoxanide”. MedlinePlus Drug Information. U.S. National Library of Medicine. 28 July 2010. Retrieved 2010-08-19.
• “Parasitic infections”. Am J Transplant. 4 (Suppl 10): 142–55. 2004. doi:10.1111/j.1600-6135.2004.00677.x. PMID 15504227.

Nitazoxanide

Clinical data
Trade names	Alinia, Nizonide, and others
AHFS/Drugs.com	Monograph
MedlinePlus	a603017
License data	US FDA: Nitazoxanide
Pregnancy category	US: B (No risk in non-human studies)
Routes of administration	Oral
Drug class	Antiprotozoal Broad-spectrum antiparasitic Broad-spectrum antiviral
ATC code	P01AX11 (WHO)
Legal status
Legal status	US: ℞-only
Pharmacokinetic data
Protein binding	Nitazoxanide: ? Tizoxanide: over 99%[1][2]
Metabolism	Rapidly hydrolyzed to tizoxanide[1]
Metabolites	tizoxanide[1][2] tizoxanide glucuronide[1][2]
Elimination half-life	3.5 hours[3]
Excretion	Renal, biliary, and fecal[1]
Identifiers
IUPAC name[show]
CAS Number	55981-09-4
PubChem CID	41684
DrugBank	DB00507
ChemSpider	38037
UNII	SOA12P041N
KEGG	D02486
ChEMBL	ChEMBL1401
NIAID ChemDB	057131
CompTox Dashboard (EPA)	DTXSID5033757
ECHA InfoCard	100.054.465
Chemical and physical data
Formula	C12H9N3O5S
Molar mass	307.283 g/mol g·mol−1
3D model (JSmol)	Interactive image
SMILES[hide] O=C(Nc1ncc(s1)[N+]([O-])=O)c2ccccc2OC(=O)C

//////////////nitazoxanide

Niclosamide

ニクロサミド;

Niclosamide, sold under the brand name Niclocide among others, is a medication used to treat tapeworm infestations.^[2] This includes diphyllobothriasis, hymenolepiasis, and taeniasis.^[2] It is not effective against other worms such as pinworms or roundworms.^[3] It is taken by mouth.^[2]

Side effects include nausea, vomiting, abdominal pain, and itchiness.^[2] It may be used during pregnancy and appears to be safe for the baby.^[2] Niclosamide is in the anthelmintic family of medications.^[3] It works by blocking the uptake of sugar by the worm.^[4]

Niclosamide was discovered in 1958.^[5] It is on the World Health Organization’s List of Essential Medicines, the safest and most effective medicines needed in a health system.^[6] The wholesale cost in the developing world is about 0.24 USD for a course of treatment.^[7] It is not commercially available in the United States.^[3] It is effective in a number of other animals.^[4]

Side effects

Side effects include nausea, vomiting, abdominal pain, constipation, and itchiness.^[2] Rarely, dizziness, skin rash, drowsiness, perianal itching, or an unpleasant taste occur. For some of these reasons, praziquantel is a preferable and equally effective treatment for tapeworm infestation.^{[citation needed]}

Mechanism of action

Niclosamide inhibits glucose uptake, oxidative phosphorylation, and anaerobic metabolism in the tapeworm.^[8]

Other applications

Niclosamide’s metabolic effects are relevant to wide ranges of organisms, and accordingly it has been applied as a control measure to organisms other than tapeworms. For example, it is an active ingredient in some formulations such as Bayluscide for killing lamprey larvae,^[9][10] as a molluscide,^[11] and as a general purpose piscicide in aquaculture. Niclosamide has a short half-life in water in field conditions; this makes it valuable in ridding commercial fish ponds of unwanted fish; it loses its activity soon enough to permit re-stocking within a few days of eradicating the previous population.^[11] Researchers have found that niclosamide is effective in killing invasive zebra mussels in cool waters.^[12]

Research

Niclosamide is being studied in a number of types of cancer.^[13] Niclosamide along with oxyclozanide, another anti-tapeworm drug, was found in a 2015 study to display “strong in vivo and in vitro activity against methicillin-resistant Staphylococcus aureus (MRSA)”.^[14]

syn

https://www.sciencedirect.com/science/article/pii/S0099542805320028

References

External links

• “Niclosamide”. Drug Information Portal. U.S. National Library of Medicine.
• Taber, Clarence Wilbur; Venes, Donald; Thomas, Clayton L. (2001). Taber’s cyclopedic medical dictionary. Philadelphia: F.A.Davis Co.
• Niclosamide in the Pesticide Properties DataBase (PPDB)
• “MedlinePlus Drug Information: Niclosamide (Oral)”. MedlinePlus. U.S. National Library of Medicine. 1995-06-23. Archived from the original on 2006-12-16.
• World Health Organization (1995). “Helminths: Cestode (tapeworm) infection: Niclosamide”. WHO model prescribing information : drugs used in parasitic diseases (2nd ed.). World Health Organization (WHO). hdl:10665/41765.

Niclosamide

Niclosamide

Clinical data
Trade names	Niclocide, Fenasal, Phenasal, others[1]
AHFS/Drugs.com	Micromedex Detailed Consumer Information
Routes of administration	By mouth
ATC code	P02DA01 (WHO) QP52AG03 (WHO)
Identifiers
IUPAC name[show]
CAS Number	50-65-7
PubChem CID	4477
DrugBank	DB06803
ChemSpider	4322
UNII	8KK8CQ2K8G
KEGG	D00436
ChEBI	CHEBI:7553
ChEMBL	ChEMBL1448
CompTox Dashboard (EPA)	DTXSID7040362
ECHA InfoCard	100.000.052
Chemical and physical data
Formula	C13H8Cl2N2O4
Molar mass	327.119 g/mol g·mol−1
3D model (JSmol)	Interactive image
Melting point	225 to 230 °C (437 to 446 °F)
SMILES[hide] Clc2cc(ccc2NC(=O)c1cc(Cl)ccc1O)[N+]([O-])=O

//////////Niclosamide ニクロサミド , никлосамид , نيكلوساميد , 氯硝柳胺 , covid 19, corona virus

CHLOROQUINE

Chloroquine is a medication used primarily to prevent and to treat malaria in areas where that parasitic disease is known to remain sensitive to its effects.^[1] A benefit of its use in therapy, when situations allow, is that it can be taken by mouth (versus by injection).^[1] Controlled studies of cases involving human pregnancy are lacking, but the drug may be safe for use for such patients.^{[verification needed][1][2]} However, the agent is not without the possibility of serious side effects at standard doses,^[1][3] and complicated cases, including infections of certain types or caused by resistant strains, typically require different or additional medication.^[1] Chloroquine is also used as a medication for rheumatoid arthritis, lupus erythematosus, and other parasitic infections (e.g., amebiasis occurring outside of the intestines).^[1] Beginning in 2020, studies have proceeded on its use as a coronavirus antiviral, in possible treatment of COVID-19.^[4]

Chloroquine, otherwise known as chloroquine phosphate, is in the 4-aminoquinoline class of drugs.^[1] As an antimalarial, it works against the asexual form of the malaria parasite in the stage of its life cycle within the red blood cell.^[1] In its use against rheumatoid arthritis and lupus erythematosus, its activity as a mild immunosuppressive underlies its mechanism.^[1] Antiviral activities, established and putative, are attributed to chloroquines inhibition of glycosylation pathways (of host receptor sialylation or virus protein post-translational modification), or to inhibition of virus endocytosis (e.g., via alkalisation of endosomes), or other possible mechanisms.^[5] Common side effects resulting from these therapeutic uses, at common doses, include muscle problems,^{[clarification needed]} loss of appetite, diarrhea, and skin rash.^{[clarification needed][1]} Serious side effects include problems with vision (retinopathy), muscle damage, seizures, and certain anemias.^[1][6]

Chloroquine was discovered in 1934 by Hans Andersag.^[7][8] It is on the World Health Organization’s List of Essential Medicines, the safest and most effective medicines needed in a health system.^[9] It is available as a generic medication.^[1] The wholesale cost in the developing world is about US$0.04.^[10] In the United States, it costs about US$5.30 per dose.^[1]

Medical uses

Malaria

Chloroquine has been used in the treatment and prevention of malaria from Plasmodium vivax, P. ovale, and P. malariae. It is generally not used for Plasmodium falciparum as there is widespread resistance to it.^[12][13]

Chloroquine has been extensively used in mass drug administrations, which may have contributed to the emergence and spread of resistance. It is recommended to check if chloroquine is still effective in the region prior to using it.^[14] In areas where resistance is present, other antimalarials, such as mefloquine or atovaquone, may be used instead. The Centers for Disease Control and Prevention recommend against treatment of malaria with chloroquine alone due to more effective combinations.^[15]

Amebiasis

In treatment of amoebic liver abscess, chloroquine may be used instead of or in addition to other medications in the event of failure of improvement with metronidazole or another nitroimidazole within 5 days or intolerance to metronidazole or a nitroimidazole.^[16]

Rheumatic disease

As it mildly suppresses the immune system, chloroquine is used in some autoimmune disorders, such as rheumatoid arthritis and lupus erythematosus.^[1]

Side effects

Side effects include blurred vision, nausea, vomiting, abdominal cramps, headache, diarrhea, swelling legs/ankles, shortness of breath, pale lips/nails/skin, muscle weakness, easy bruising/bleeding, hearing and mental problems.^[17][18]

• Unwanted/uncontrolled movements (including tongue and face twitching) ^[17]
• Deafness or tinnitus.^[17]
• Nausea, vomiting, diarrhea, abdominal cramps^[18]
• Headache.^[17]
• Mental/mood changes (such as confusion, personality changes, unusual thoughts/behavior, depression, feeling being watched, hallucinating)^[17][18]
• Signs of serious infection (such as high fever, severe chills, persistent sore throat)^[17]
• Skin itchiness, skin color changes, hair loss, and skin rashes.^[18][19]
  • Chloroquine-induced itching is very common among black Africans (70%), but much less common in other races. It increases with age, and is so severe as to stop compliance with drug therapy. It is increased during malaria fever; its severity is correlated to the malaria parasite load in blood. Some evidence indicates it has a genetic basis and is related to chloroquine action with opiate receptors centrally or peripherally.^[20]
• Unpleasant metallic taste
  • This could be avoided by “taste-masked and controlled release” formulations such as multiple emulsions.^[21]
• Chloroquine retinopathy
• Electrocardiographic changes^[22]
  • This manifests itself as either conduction disturbances (bundle-branch block, atrioventricular block) or Cardiomyopathy – often with hypertrophy, restrictive physiology, and congestive heart failure. The changes may be irreversible. Only two cases have been reported requiring heart transplantation, suggesting this particular risk is very low. Electron microscopy of cardiac biopsies show pathognomonic cytoplasmic inclusion bodies.
• Pancytopenia, aplastic anemia, reversible agranulocytosis, low blood platelets, neutropenia.^[23]

Pregnancy

Chloroquine has not been shown to have any harmful effects on the fetus when used for malarial prophylaxis.^[24] Small amounts of chloroquine are excreted in the breast milk of lactating women. However, this drug can be safely prescribed to infants, the effects are not harmful. Studies with mice show that radioactively tagged chloroquine passed through the placenta rapidly and accumulated in the fetal eyes which remained present five months after the drug was cleared from the rest of the body.^[23][25] Women who are pregnant or planning on getting pregnant are still advised against traveling to malaria-risk regions.^[24]

Elderly

There is not enough evidence to determine whether chloroquine is safe to be given to people aged 65 and older. Since it is cleared by the kidneys, toxicity should be monitored carefully in people with poor kidney functions.^[23]

Drug interactions

Chloroquine has a number of drug-drug interactions that might be of clinical concern:^{[citation needed]}

• Ampicillin– levels may be reduced by chloroquine;^[23]
• Antacids– may reduce absorption of chloroquine;^[23]
• Cimetidine– may inhibit metabolism of chloroquine; increasing levels of chloroquine in the body;^[23]
• Cyclosporine– levels may be increased by chloroquine;^[23] and
• Mefloquine– may increase risk of convulsions.^[23]

Overdose

Chloroquine is very dangerous in overdose. It is rapidly absorbed from the gut. In 1961, a published compilation of case reports contained accounts of three children who took overdoses and died within 2.5 hours of taking the drug. While the amount of the overdose was not stated, the therapeutic index for chloroquine is known to be small.^[26] One of the children died after taking 0.75 or 1 gram, or twice a single therapeutic amount for children. Symptoms of overdose include headache, drowsiness, visual disturbances, nausea and vomiting, cardiovascular collapse, seizures, and sudden respiratory and cardiac arrest.^[23]

An analog of chloroquine – hydroxychloroquine – has a long half-life (32–56 days) in blood and a large volume of distribution (580–815 L/kg).^[27] The therapeutic, toxic and lethal ranges are usually considered to be 0.03 to 15 mg/l, 3.0 to 26 mg/l and 20 to 104 mg/l, respectively. However, nontoxic cases have been reported up to 39 mg/l, suggesting individual tolerance to this agent may be more variable than previously recognised.^[27]

Pharmacology

Chloroquine’s absorption of the drug is rapid. It is widely distributed in body tissues. It’s protein binding is 55%.^[ It’s metabolism is partially hepatic, giving rise to its main metabolite, desethylchloroquine. It’s excretion os ≥50% as unchanged drug in urine, where acidification of urine increases its elimination It has a very high volume of distribution, as it diffuses into the body’s adipose tissue.

Accumulation of the drug may result in deposits that can lead to blurred vision and blindness. It and related quinines have been associated with cases of retinal toxicity, particularly when provided at higher doses for longer times. With long-term doses, routine visits to an ophthalmologist are recommended.

Chloroquine is also a lysosomotropic agent, meaning it accumulates preferentially in the lysosomes of cells in the body. The pK_a for the quinoline nitrogen of chloroquine is 8.5, meaning—in simplified terms, considering only this basic site—it is about 10% deprotonated at physiological pH (per the Henderson-Hasselbalch equation) This decreases to about 0.2% at a lysosomal pH of 4.6.Because the deprotonated form is more membrane-permeable than the protonated form, a quantitative “trapping” of the compound in lysosomes results.

Mechanism of action

Malaria

The lysosomotropic character of chloroquine is believed to account for much of its antimalarial activity; the drug concentrates in the acidic food vacuole of the parasite and interferes with essential processes. Its lysosomotropic properties further allow for its use for in vitro experiments pertaining to intracellular lipid related diseases,^[28][29] autophagy, and apoptosis.^[30]

Inside red blood cells, the malarial parasite, which is then in its asexual lifecycle stage, must degrade hemoglobin to acquire essential amino acids, which the parasite requires to construct its own protein and for energy metabolism. Digestion is carried out in a vacuole of the parasitic cell.^{[citation needed]}

Hemoglobin is composed of a protein unit (digested by the parasite) and a heme unit (not used by the parasite). During this process, the parasite releases the toxic and soluble molecule heme. The heme moiety consists of a porphyrin ring called Fe(II)-protoporphyrin IX (FP). To avoid destruction by this molecule, the parasite biocrystallizes heme to form hemozoin, a nontoxic molecule. Hemozoin collects in the digestive vacuole as insoluble crystals.^{[citation needed]}

Chloroquine enters the red blood cell by simple diffusion, inhibiting the parasite cell and digestive vacuole. Chloroquine then becomes protonated (to CQ2+), as the digestive vacuole is known to be acidic (pH 4.7); chloroquine then cannot leave by diffusion. Chloroquine caps hemozoin molecules to prevent further biocrystallization of heme, thus leading to heme buildup. Chloroquine binds to heme (or FP) to form the FP-chloroquine complex; this complex is highly toxic to the cell and disrupts membrane function. Action of the toxic FP-chloroquine and FP results in cell lysis and ultimately parasite cell autodigestion. ^[31] Parasites that do not form hemozoin are therefore resistant to chloroquine.^[32]

Resistance in malaria[edit source]

Since the first documentation of P. falciparum chloroquine resistance in the 1950s, resistant strains have appeared throughout East and West Africa, Southeast Asia, and South America. The effectiveness of chloroquine against P. falciparum has declined as resistant strains of the parasite evolved. They effectively neutralize the drug via a mechanism that drains chloroquine away from the digestive vacuole. Chloroquine-resistant cells efflux chloroquine at 40 times the rate of chloroquine-sensitive cells; the related mutations trace back to transmembrane proteins of the digestive vacuole, including sets of critical mutations in the P. falciparum chloroquine resistance transporter (PfCRT) gene. The mutated protein, but not the wild-type transporter, transports chloroquine when expressed in Xenopus oocytes (frog’s eggs) and is thought to mediate chloroquine leak from its site of action in the digestive vacuole.^[33] Resistant parasites also frequently have mutated products of the ABC transporter P. falciparum multidrug resistance (PfMDR1) gene, although these mutations are thought to be of secondary importance compared to Pfcrt. Verapamil, a Ca²⁺ channel blocker, has been found to restore both the chloroquine concentration ability and sensitivity to this drug. Recently, an altered chloroquine-transporter protein CG2 of the parasite has been related to chloroquine resistance, but other mechanisms of resistance also appear to be involved.^[34] Research on the mechanism of chloroquine and how the parasite has acquired chloroquine resistance is still ongoing, as other mechanisms of resistance are likely.^{[citation needed]}

Other agents which have been shown to reverse chloroquine resistance in malaria are chlorpheniramine, gefitinib, imatinib, tariquidar and zosuquidar.^[35]

Antiviral

Chloroquine has antiviral effects.^[36] It increases late endosomal or lysosomal pH, resulting in impaired release of the virus from the endosome or lysosome – release requires a low pH. The virus is therefore unable to release its genetic material into the cell and replicate.^[37][38]

Chloroquine also seems to act as a zinc ionophore, that allows extracellular zinc to enter the cell and inhibit viral RNA-dependent RNA polymerase.^[39][40]

Other

Chloroquine inhibits thiamine uptake.^[41] It acts specifically on the transporter SLC19A3.

Against rheumatoid arthritis, it operates by inhibiting lymphocyte proliferation, phospholipase A2, antigen presentation in dendritic cells, release of enzymes from lysosomes, release of reactive oxygen species from macrophages, and production of IL-1.

History

In Peru the indigenous people extracted the bark of the Cinchona plant^[42] trees and used the extract (Chinchona officinalis) to fight chills and fever in the seventeenth century. In 1633 this herbal medicine was introduced in Europe, where it was given the same use and also began to be used against malaria.^[43] The quinoline antimalarial drug quinine was isolated from the extract in 1820, and chloroquine is an analogue of this.

Chloroquine was discovered in 1934, by Hans Andersag and coworkers at the Bayer laboratories, who named it “Resochin”.^[44] It was ignored for a decade, because it was considered too toxic for human use. During World War II, United States government-sponsored clinical trials for antimalarial drug development showed unequivocally that chloroquine has a significant therapeutic value as an antimalarial drug. It was introduced into clinical practice in 1947 for the prophylactic treatment of malaria.^[45]

Society and culture

Formulations

Chloroquine comes in tablet form as the phosphate, sulfate, and hydrochloride salts. Chloroquine is usually dispensed as the phosphate.^[46]

Names

Brand names include Chloroquine FNA, Resochin, Dawaquin, and Lariago.^[47]

Other animals

Chloroquine is used to control the aquarium fish parasite Amyloodinium ocellatum.^[48]

Research

COVID-19

In late January 2020 during the 2019–20 coronavirus outbreak, Chinese medical researchers stated that exploratory research into chloroquine and two other medications, remdesivir and lopinavir/ritonavir, seemed to have “fairly good inhibitory effects” on the SARS-CoV-2 virus, which is the virus that causes COVID-19. Requests to start clinical testing were submitted.^[49] Chloroquine had been also proposed as a treatment for SARS, with in vitro tests inhibiting the SARS-CoV virus.^[50][51]

Chloroquine has been recommended by Chinese, South Korean and Italian health authorities for the treatment of COVID-19.^[52][53] These agencies noted contraindications for people with heart disease or diabetes.^[54] Both chloroquine and hydroxychloroquine were shown to inhibit SARS-CoV-2 in vitro, but a further study concluded that hydroxychloroquine was more potent than chloroquine, with a more tolerable safety profile.^[55] Preliminary results from a trial suggested that chloroquine is effective and safe in COVID-19 pneumonia, “improving lung imaging findings, promoting a virus-negative conversion, and shortening the disease course.”^[56] Self-medication with chloroquine has caused one known fatality.^[57]

On 24 March 2020, NBC News reported^[58] a fatality due to misuse of a chloroquine product used to control fish parasites.^[59]

Other viruses

In October 2004, a group of researchers at the Rega Institute for Medical Research published a report on chloroquine, stating that chloroquine acts as an effective inhibitor of the replication of the severe acute respiratory syndrome coronavirus (SARS-CoV) in vitro.^[60]

Chloroquine was being considered in 2003, in pre-clinical models as a potential agent against chikungunya fever.^[61]

Other

The radiosensitizing and chemosensitizing properties of chloroquine are beginning to be exploited in anticancer strategies in humans.^[62][63] In biomedicinal science, chloroquine is used for in vitro experiments to inhibit lysosomal degradation of protein products.

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References