RESUMO
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.
Assuntos
Serina/análogos & derivados , Trombina/antagonistas & inibidores , Animais , Sítios de Ligação , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Fibrinolíticos/síntese química , Fibrinolíticos/química , Fibrinolíticos/farmacologia , Humanos , Camundongos , Ácidos Nipecóticos/síntese química , Ácidos Nipecóticos/química , Ácidos Nipecóticos/farmacologia , Ratos , Serina/síntese química , Serina/química , Serina/farmacologia , Inibidores de Serina Proteinase/síntese química , Inibidores de Serina Proteinase/química , Inibidores de Serina Proteinase/farmacologia , Relação Estrutura-Atividade , Especificidade por Substrato , Trombina/química , Trombose/tratamento farmacológico , Trombose/prevenção & controleRESUMO
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.
