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ChemMedChem ; 16(24): 3672-3690, 2021 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-34278727

RESUMO

Herein we report a microscale parallel synthetic approach allowing for rapid access to libraries of N-acylated aminotriazoles and screening of their inhibitory activity against factor XIIa (FXIIa) and thrombin, which are targets for antithrombotic drugs. This approach, in combination with post-screening structure optimization, yielded a potent 7 nM inhibitor of FXIIa and a 25 nM thrombin inhibitor; both compounds showed no inhibition of the other tested serine proteases. Selected N-acylated aminotriazoles exhibited anticoagulant properties in vitro influencing the intrinsic blood coagulation pathway, but not extrinsic coagulation. Mechanistic studies of FXIIa inhibition suggested that synthesized N-acylated aminotriazoles are covalent inhibitors of FXIIa. These synthesized compounds may serve as a promising starting point for the development of novel antithrombotic drugs.


Assuntos
Amitrol (Herbicida)/farmacologia , Anticoagulantes/farmacologia , Fator XIIa/antagonistas & inibidores , Inibidores de Serina Proteinase/farmacologia , Trombina/antagonistas & inibidores , Acilação , Amitrol (Herbicida)/síntese química , Amitrol (Herbicida)/química , Anticoagulantes/síntese química , Anticoagulantes/química , Coagulação Sanguínea/efeitos dos fármacos , Relação Dose-Resposta a Droga , Fator XIIa/metabolismo , Humanos , Estrutura Molecular , Inibidores de Serina Proteinase/síntese química , Inibidores de Serina Proteinase/química , Relação Estrutura-Atividade , Trombina/metabolismo
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