title: Discovery of transition state factor Xa inhibitors as potential anticoagulant agents.
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 [1-4].
authors.affiliation: Department of Medicinal Chemistry, COR Therapeutics, Inc., South San Francisco, CA 94080, USA. BZHU@corr.com
authors.forename: B Y
authors.initials: BY
authors.lastname: Zhu
authors.forename: W
authors.initials: W
authors.lastname: Huang
authors.forename: T
authors.initials: T
authors.lastname: Su
authors.forename: C
authors.initials: C
authors.lastname: Marlowe
authors.forename: U
authors.initials: U
authors.lastname: Sinha
authors.forename: S
authors.initials: S
authors.lastname: Hollenbach
authors.forename: R M
authors.initials: RM
authors.lastname: Scarborough
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001583:Benzoxazoles / Q000138:chemical synthesis / Q000494:pharmacology; D015195:Drug Design; D005165:Factor V / Q000187:drug effects; D015951:Factor Xa / Q000187:drug effects; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D007769:Lactams / Q000138:chemical synthesis / Q000494:pharmacology; D009842:Oligopeptides / Q000737:chemistry; D010879:Piperazines / Q000138:chemical synthesis / Q000494:pharmacology; D011817:Rabbits; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000494:pharmacology; D013844:Thiazoles / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: D000925:Anticoagulants; D001583:Benzoxazoles; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D007769:Lactams; D009842:Oligopeptides; D010879:Piperazines; D013449:Sulfonamides; D013844:Thiazoles; C022475:prothrombinase complex; C015608:benzoyl-Ile-Glu-Gly-Arg-p-nitroanilide; D005165:Factor V; D015951:Factor Xa