title: The discovery of the Factor Xa inhibitor otamixaban: from lead identification to clinical development.
abstract: Factor Xa (fXa) is a critical serine protease situated at the confluence of the intrinsic and extrinsic pathways of the blood coagulation cascade. FXa catalyses the conversion of prothrombin to thrombin via the prothrombinase complex. Its singular role in thrombin generation, coupled with its potentiating effects on clot formation render it an attractive target for therapeutic intervention. Otamixaban is a synthetically derived parenteral fXa inhibitor currently in late stage clinical development at Sanofi-Aventis for the management of acute coronary syndrome. Otamixaban is a potent (Ki = 0.5 nM), selective, rapid acting, competitive and reversible fXa inhibitor that effectively inhibits both free and prothrombinase-bound fXa. In vivo experiments have demonstrated that Otamixaban is highly efficacious in rodent, canine and porcine models of thrombosis. In addition, recent clinical findings indicate that Otamixaban is efficacious, safe and well tolerated in humans and therefore has considerable potential for the treatment of acute coronary syndrome. This review article chronicles the discovery and pre-clinical data surrounding the fXa inhibitor Otamixaban as well as the recent clinical findings in humans.
authors.affiliation: Department of Discovery Chemistry, Roche Research Center, 340 Kingsland St., Nutley, New Jersey 07110, USA. Kevin.Guertin@Roche.com
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Guertin
authors.forename: Yong-Mi
authors.initials: YM
authors.lastname: Choi
mesh_terms: D000818:Animals; D002986:Clinical Trials as Topic; D003497:Cyclic N-Oxides / Q000737:chemistry / Q000494:pharmacology*; D004285:Dogs; D015195:Drug Design; D004952:Esters / Q000737:chemistry; D065427:Factor Xa Inhibitors; D000882:Haplorhini; D006801:Humans; D051379:Mice; D008954:Models, Biological; D008956:Models, Chemical; D008968:Molecular Conformation; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D011817:Rabbits; D012697:Serine Endopeptidases / Q000737:chemistry; D015398:Signal Transduction; D016896:Treatment Outcome
chemical_list: D003497:Cyclic N-Oxides; D004952:Esters; D065427:Factor Xa Inhibitors; D011725:Pyridines; D012697:Serine Endopeptidases; C435830:otamixaban