RESUMO
The design, synthesis and biological activity of a series of novel non-covalent D-Phe-Pro-Arg motif-based thrombin inhibitors incorporating 4,5,6,7-tetrahydrobenzothiazol-2-amine as a novel arginine surrogate are described. Compound 9, the most potent in the series of thrombin inhibitors, exhibited an in vitro K(i) of 128 nM and 342-fold selectivity against trypsin. The binding mode of this novel class of thrombin inhibitors in the enzyme active site, based on the X-ray crystal structure of compound 9 co-crystallized with human alpha-thrombin, is discussed.
Assuntos
Arginina/química , Materiais Biomiméticos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Tiazóis/farmacologia , Trombina/antagonistas & inibidores , Tripsina/metabolismo , Sítios de Ligação , Materiais Biomiméticos/química , Cristalografia por Raios X , Humanos , Modelos Moleculares , Estrutura Molecular , Ligação Proteica , Relação Estrutura-Atividade , Especificidade por Substrato , Trombina/metabolismoRESUMO
Novel, highly selective and potent thrombin inhibitors were identified as a result of combing the 3-benzylsulfonylamino-2-pyridinone acetamide P(2)-P(3) surrogate with weakly basic partially saturated heterobicyclic P(1)-arginine mimetics 1-8. The design, synthesis, biological activity, and the binding modes of non-covalent thrombin inhibitors featuring P(1)-4,5,6,7-tetrahydroindazole, 5,6,7,8-tetrahydroquinazoline, and 4,5,6,7-tetrahydrobenzothiazole moieties are described.
