Discovery of Transition State Factor Xa Inhibitors as Potential Anticoagulant Agents

Bing-Yan      Zhu; Wenrong      Huang; Ting      Su; Charles      Marlowe; Uma      Sinha; Stan      Hollenbach; Robert   M.   Scarborough

doi:10.2174/1568026013395425

Abstract

Factor Xa is an attractive biological target in the discovery and development of either parenteral or orally active anticoagulant agents. Several strategies have been utilized at COR Therapeutics in the pursuit of tri-peptide based transition state mimetic factor Xa inhibitors with high aqueous solubility. Some of these inhibitors have displayed excellent in vitro potency in inhibiting factor Xa in the prothrombinase complex. More importantly, these compounds showed strong in vivo antithrombotic efficacy without significant bleeding complications in several animal thrombosis models. These results demonstrated that small molecule factor Xa inhibitors could be advantageous over Warfarin and LMWH. For the discovery and development of orally active anticoagulant agents, small organic molecules as reversible factor Xa inhibitors were explored. From a medicinal chemistry perspective, significant insight has been gained regarding the in vivo antithrombotic efficacy and pharmacokinetic behaviors of each class of factor Xa inhibitors. This review will focus on the design and discovery of transition state factor Xa inhibitors as potential parenteral anticoagulant agents. Several excellent comprehensive review articles on factor Xa inhibitors have appeared recently

Keywords: Factor Xa Inhibitors, Anticoagulant Agents, ketothiazole, TRI-PEPTIDE, Factor Xa, Activated protein C, Tissue plasminogen activator