ABSTRACT
A series of retro-binding inhibitors of human alpha-thrombin was prepared to elucidate structure-activity relationships (SAR) and optimize in vivo performance. Compounds 9 and 11, orally active inhibitors of thrombin catalytic activity, were identified to be efficacious in a thrombin-induced lethality model in mice.
Subject(s)
Oligopeptides/chemical synthesis , Oligopeptides/pharmacology , Serine Proteinase Inhibitors/chemical synthesis , Serine Proteinase Inhibitors/pharmacology , Thrombin/antagonists & inhibitors , Animals , Binding Sites/drug effects , Catalysis , Humans , Mice , Structure-Activity Relationship , Thrombin/chemistry , Thrombin/toxicityABSTRACT
A series of structurally novel small molecule inhibitors of human alpha-thrombin was prepared to elucidate their structure- activity relationships (SAR), selectivity and activity in vivo. BMS-189090 (5) is identified as a potent, selective, and reversible inhibitor of human alpha-thrombin that is efficacious in vivo in a mice lethality model, and in inhibiting both arterial and venous thrombosis in a rat model.
Subject(s)
Serine/analogs & derivatives , Thrombin/antagonists & inhibitors , Animals , Binding Sites , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Design , Drug Evaluation, Preclinical , Fibrinolytic Agents/chemical synthesis , Fibrinolytic Agents/chemistry , Fibrinolytic Agents/pharmacology , Humans , Mice , Nipecotic Acids/chemical synthesis , Nipecotic Acids/chemistry , Nipecotic Acids/pharmacology , Rats , Serine/chemical synthesis , Serine/chemistry , Serine/pharmacology , Serine Proteinase Inhibitors/chemical synthesis , Serine Proteinase Inhibitors/chemistry , Serine Proteinase Inhibitors/pharmacology , Structure-Activity Relationship , Substrate Specificity , Thrombin/chemistry , Thrombosis/drug therapy , Thrombosis/prevention & controlABSTRACT
A series of structurally novel small molecule inhibitors of human alpha-thrombin was prepared to elucidate their structure-activity relationships (SARs), selectivity and activity in vivo. BMS-189664 (3) is identified as a potent, selective, and orally active reversible inhibitor of human alpha-thrombin which is efficacious in vivo in a mouse lethality model, and at inhibiting both arterial and venous thrombosis in cynomolgus monkey models.
