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.

New Anticoagulants

“…35 These features render otamixaban an attractive candidate to replace heparin in patients with ACS. 36 This possibility was evaluated in the Study of Otamixaban Versus Unfractionated Heparin (UFH) and Eptifibatide in Non-ST Elevation Acute Coronary Syndrome (SEPIA-ACS) 1-Thrombolysis in Myocardial Infarction (TIMI) 42, a phase II dose-finding study that compared 5 different doses of otamixaban with the combination of heparin plus eptifibatide for the prevention of major cardiovascular events in 3241 patients with non-ST-segment elevation ACS.…”

Developments in factor Xa inhibitors for the treatment of thromboembolic disorders

“…241 A detailed account of the development of this compound has been disclosed. 242 Based on the ethylenediamine series found in 145-148 (Fig. 28), a series of b-amino acid esters was prepared.…”

Orale, direkte Thrombin‐ und Faktor‐Xa‐Hemmer: Kommt die Ablösung für Warfarin, Blutegel und Schweinedärme?

“…[49c] Otamixaban (33) [50] von Aventis befindet sich in Phase III der klinischen [42] Das bei Rivaroxaban vorliegende Kombinationsmuster aus P1-und P4-Rest erwies sich als besonders effizient und wurde auch bei anderen Grundkörpern wie 35 [52] und 50 adaptiert. Razaxaban (37; Schema 14) war in Phase II der klinischen Entwicklung.…”