Ciraparantag, Aripazine

Ciraparantag
PER977， Aripazine
CAS Number:1438492-26-2
Chemical Name:N1,N1-[piperazine-1,4-diylbis(propane-1,3-diyl)]bis-L-argininamide

(2S,2’S)-N,N’-(Piperazine-1,4-diyldipropane-3,1-diyl)bis(2-amino-5-carbamimidamidopentanamide)

2S,2’S)-N,N’-(piperazine-1,4-diylbis(propane-3,1-diyl))bis(2-amino-5-guanidinopentanamide)

C22H48N12O2
Mw: 512.40232
Mechanism of Action: an intravenously administered anticoagulant Reversal Agent

Blood coagulation factor modulators; Factor Xa inhibitors
Indication: Anticoagulant Reversal
Development Stage: Phase II
Developer:Perosphere, Inc..Perosphere Inc.

Highest Development Phases

• Phase IIHaemorrhage

Most Recent Events

• 02 Apr 2015Ciraparantag receives Fast Track designation for Haemorrhage [IV] (In volunteers) in USA
• 05 Nov 2014Efficacy and adverse events data from a phase I/II trial in Haemorrhage released by Perosphere
• 06 Oct 2014Aripazine is available for licensing as of 06 Oct 2014. http://www.perosphere.com/

Aripazine（PER977, ciraparantag）

Ciraparantag, also known as PER977, is a A Small Molecule Reversal Agent for New Oral Anticoagulants and Heparins. PER977 is water-soluble, cationic molecule that is designed to bind specifically to unfractionated heparin and low-molecular-weight heparin through noncovalent hydrogen bonding and charge–charge interactions.

PER-977 is an intravenous heparin neutralizer in phase II clinical trials at Perosphere to reverse edoxaban’s induced anticoagulation.

In April 2015, fast track designation was assigned in the U.S. as an investigational anticoagulant reversal agent.

WO 2013082210

http://www.google.com/patents/WO2013082210A1?cl=en

In one scheme, the compound of Formula V (DAP)

is synthesized by reacting excess equivalents (e.g., at least about two equivalents) of compound 1

with one equivalent of compound 2

in the presence of a peptide coupling reagent, to obtain a compound 3

wherein PI is a protecting group and P2 is a protecting group or is a hydrogen.

the coupling involved reacting compound 1, wherein PI was Boc and P2 was a hydrogen (depicted as Boc-Arg-OH HCl below), with compound 2 as depicted below:

The resultant crude product was more than 95% pure by thin layer

chromatography (TLC).

Subsequently, the deprotection step was carried out as depicted below:

The deprotected product was purified by preparative HPLC using 1% acetic acid buffer. Product purity of >98% was observed. Residual TFA was removed by low quantity of DOWEX resin. The molecular weight of DAP (the compound of Formula V) is 512.4, and the compound synthesized according to the above scheme exhibited the following primary peak by mass spectroscopy: [M+H]⁺=513.4.

1: Dzik WH. Reversal of oral factor Xa inhibitors by prothrombin complex concentrates: a re-appraisal. J Thromb Haemost. 2015 Jun;13 Suppl 1:S187-94. doi: 10.1111/jth.12949. PubMed PMID: 26149022.

2: Crowther M, Crowther MA. Antidotes for Novel Oral Anticoagulants: Current Status and Future Potential. Arterioscler Thromb Vasc Biol. 2015 Aug;35(8):1736-45. doi: 10.1161/ATVBAHA.114.303402. Epub 2015 Jun 18. PubMed PMID: 26088576.

3: Sullivan DW Jr, Gad SC, Laulicht B, Bakhru S, Steiner S. Nonclinical Safety Assessment of PER977: A Small Molecule Reversal Agent for New Oral Anticoagulants and Heparins. Int J Toxicol. 2015 Jun 15. pii: 1091581815590667. [Epub ahead of print] PubMed PMID: 26079256.

4: Mo Y, Yam FK. Recent advances in the development of specific antidotes for target-specific oral anticoagulants. Pharmacotherapy. 2015 Feb;35(2):198-207. doi: 10.1002/phar.1532. Epub 2015 Feb 3. PubMed PMID: 25644580.

5: Yates SW. Interrupting anticoagulation in patients with nonvalvular atrial fibrillation. P T. 2014 Dec;39(12):858-80. PubMed PMID: 25516695; PubMed Central PMCID: PMC4264672.

6: Vanden Daelen S, Peetermans M, Vanassche T, Verhamme P, Vandermeulen E. Monitoring and reversal strategies for new oral anticoagulants. Expert Rev Cardiovasc Ther. 2015 Jan;13(1):95-103. doi: 10.1586/14779072.2015.987126. Epub 2014 Nov 28. PubMed PMID: 25431993.

7: Costin J, Ansell J, Laulicht B, Bakhru S, Steiner S. Reversal agents in development for the new oral anticoagulants. Postgrad Med. 2014 Nov;126(7):19-24. doi: 10.3810/pgm.2014.11.2829. Review. PubMed PMID: 25387210.

8: Ansell JE, Bakhru SH, Laulicht BE, Steiner SS, Grosso M, Brown K, Dishy V, Noveck RJ, Costin JC. Use of PER977 to reverse the anticoagulant effect of edoxaban. N Engl J Med. 2014 Nov 27;371(22):2141-2. doi: 10.1056/NEJMc1411800. Epub 2014 Nov 5. PubMed PMID: 25371966.

9: Hankey GJ. Intracranial hemorrhage and novel anticoagulants for atrial fibrillation: what have we learned? Curr Cardiol Rep. 2014 May;16(5):480. doi: 10.1007/s11886-014-0480-9. Review. PubMed PMID: 24643903.

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