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Ciraparantag, Aripazine

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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)

Figure imgf000025_0001

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

Figure imgf000025_0002

with one equivalent of compound 2

Figure imgf000025_0003

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

Figure imgf000026_0001

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:

Figure imgf000027_0001

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

chromatography (TLC).

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

Figure imgf000027_0002

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.

References

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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DR ANTHONY CRASTO

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 29 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 29 year tenure till date Aug 2016, Around 30 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 25 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 13 lakh plus views on New Drug Approvals Blog in 212 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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