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DAREXABAN, TANEXABAN

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DAREXABAN , TANEXABAN

N-(3-Hydroxy-2-{[4-(4-methyl-1,4-diazepan-1-yl)benzoyl]amino}phenyl)-4-methoxybenzamide

365462-23-3 365462-24-4 (maleate) 

365462-23-3, Darexaban,UNII-KF322K101S
N-(2-Hydroxy-6-(4-methoxybenzamido)phenyl)-4-(4-methyl-1,4-diazepan-1-yl)benzamide, Darexaban [INN]
Molecular Formula: C27H30N4O4   Molecular Weight: 474.5515

Darexaban (YM150) is a direct inhibitor of factor Xa created by Astellas Pharma.[1] It is an experimental drug that acts as ananticoagulant and antithrombotic to prevent venous thromboembolism after a major orthopaedic surgery, stroke in patients with atrial fibrillation[2] and possibly ischemic events in acute coronary syndrome.[3] It is used in form of the maleate. The development of darexaban was discontinued in September 2011.

Factor Xa

Factor Xa (FXa) is an essential blood coagulation factor[2] that is responsible for the initiation of the coagulation cascade. FXa cleaves prothrombin to its active form thrombin, which then acts to convert soluble fibrinogen to insoluble fibrin and to activateplatelets. Stabilization of the platelet aggregation by fibrin mesh ultimately leads to clot formation.[4]

Metabolism

Darexaban is rapidly absorbed and extensively metabolized in the liver to its active metabolite, darexaban glucuronide (YM-222714) during first pass metabolism via glucuronidation.[5] The metabolism of darexaban also occurs in the small intestine but to a much lesser extent.[2] Glucuronidation of darexaban occurs quickly, thus the half life of darexaban itself is short. However, the resultant darexaban glucuronide metabolite has a long half life of approximately 14-18 hours, reaching its maximum levels in the blood 1-1.5 hour post dose.[2] As a result, darexaban glucuronide is the main determinant of the antithrombotic effects.[3] Darexaban shows minimal interaction with food and is excreted through the kidneys (urine) and feces.[6]

Mechanism of action

Darexaban and darexaban glucuronide selectively and competitively inhibit FXa, suppressing prothrombin activity at the sites of blood clot (thrombus) formation. This leads to a decrease in blood clot formation in a dose dependent manner.[2] Reducing blood clot formation will decrease blood flow blockages, thus possibly lowering the risk of myocardial infarctionunstable anginavenous thrombosis, and ischemic stroke.[7]

Clinical uses

Atrial fibrillation

Atrial fibrillation is an abnormal heart rhythm that causes a reduction in the cardiac output and blood flow to the brain. It also promotes the formation of blood clots in the atria.[4]Atrial fibrillation is associated with an increased risk of embolic stroke due to the increased risk of blood clot development.[8] Oral anticoagulant drugs such as Darexaban decrease the incidence and severity of stroke in patients with atrial fibrillation by preventing the formation of blood clots.[9]

Contraindictions

The RUBY-1 phase II trial results show that oral administration of darexaban in combination with the standard dual antiplatelet therapy used for ACS patients caused a two- to four-fold increase in bleeding rates and no effect on ACS.[6] Though there were no cases of fatal bleeding or intracranial haemorrhage, the results of this study questions the concept of adding an oral anticoagulant to standard of care dual antiplatelet therapy in order to prevent recurrent ischemic events after ACS. The developpement of darexaban was discontinued in september 2011.

References

  1. Eriksson, B., et al. “A dose escalation study of YM150, an oral direct factor Xa inhibitor, in the prevention of venous thromboembolism in elective primary hip replacement surgery.” Journal of Thrombosis and Haemostasis (2007): 1660-1665
  2. Yoshiyuki, I., et al. “Biochemical and pharmalogical profile of darexaban, an oral direct Xa inhibitor.” European Journal of Pharmacology (2011): 49-55
  3.  Toshifumi, S., et al. “Identification of UDP-Glucuronosyltransferases Responsible for the Glucuronidation of Darexaban, an Oral Factor Xa Inhibitor, in Human Liver anD Intestine.” The American Society for Pharmacology and Experimental Therapeutics (2011): 278-282
  4. Katsung, B., S. Masters and A. Trevor. Basic and Clinical Pharmacology 11th Edition. United States of America: McGraw-Hill, 2009
  5.  Turpie, A., et al. “Prevention of venous thromboembolism with an oral factor Xa inhibitor, YM150, after total hip arthoplasty. A dose finding study (ONYX-2).” Journal of Thrombosis and Haemostasis (2010): 714-721
  6. Steg, PG; Mehta, SR; Jukema, JW; Lip, GY; Gibson, CM; Kovar, F; Kala, P; Garcia-Hernandez, A; Renfurm, RW; Granger, CB; Ruby-1, Investigators (2011). “RUBY-1: A randomized, double-blind, placebo-controlled trial of the safety and tolerability of the novel oral factor Xa inhibitor darexaban (YM150) following acute coronary syndrome”.European heart journal 32 (20): 2541–54. doi:10.1093/eurheartj/ehr334.PMC 3295208PMID 21878434.
  7.  Hirayama, F., et al. “Discovery of N-[2-Hydroxy-6-(4-methoxybenamido)phenyl]-4-(4-methyl-1,4-diazepan-1-yl)benzamide (Darexaban, YM150) as a Potent and Orally Available Factor Xa Inhibitor.” Journal of Medicinal Chemistry (2011): 8051-8065
  8.  Zhong, Y., et al. “Atrial Fibrillation as a Risk Factor for Stroke: A Retrospective Cohort Study of Hospitalized Medicare Beneficiaries.” American Journal of Public Health (1998): 395-400
  9.  Hylek, E., et al. “Effect of intesity of oral anticoagulation on stroke severity and mortality in atrial fibrillation.” The New England Journal of Medicine (2003): 1019-26
6-11-2010
PHARMACEUTICAL COMPOSITION FOR ORAL ADMINISTRATION
12-12-2007
Diazepan derivatives or salts thereof
11-5-2003
Diazepan derivatives or salts thereof

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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 30 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, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, 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 Open superstar 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 30 year tenure till date Dec 2017, Around 35 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, 50 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 19 lakh plus views on New Drug Approvals Blog in 216 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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