RESUMO
We describe the structure-activity relationship of the C1-group of pyrano[3,4-b]indole based inhibitors of HCV NS5B polymerase. Further exploration of the allosteric binding site led to the discovery of the significantly more potent compound 12.
Assuntos
Antivirais/química , Inibidores Enzimáticos/química , Indóis/química , Piranos/química , Proteínas não Estruturais Virais/antagonistas & inibidores , Antivirais/síntese química , Antivirais/farmacologia , Sítios de Ligação , Cristalografia por Raios X , Descoberta de Drogas , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Indóis/síntese química , Indóis/farmacologia , Piranos/síntese química , Piranos/farmacologia , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/metabolismoRESUMO
We have discovered that phenyltriazolinone is a novel and potent P1 moiety for coagulation factor Xa. X-ray structures of the inhibitors with a phenyltriazolinone in the P1 position revealed that the side chain of Asp189 has reoriented resulting in a novel S1 binding pocket which is larger in size to accommodate the phenyltriazolinone P1 substrate.
Assuntos
Anticoagulantes/síntese química , Desenho de Fármacos , Inibidores do Fator Xa , Isoxazóis/síntese química , Pirazóis/síntese química , Piridonas/síntese química , Sulfonas/síntese química , Anticoagulantes/química , Anticoagulantes/farmacologia , Cristalografia por Raios X , Humanos , Isoxazóis/química , Isoxazóis/farmacologia , Modelos Moleculares , Estrutura Molecular , Pirazóis/química , Pirazóis/farmacologia , Piridonas/química , Piridonas/farmacologia , Sulfonas/química , Sulfonas/farmacologiaRESUMO
Attempts to further optimize the pyrazole factor Xa inhibitors centered on masking the aryl aniline P4 moiety. Scaffold optimization resulted in the identification of a novel bicyclic pyrazolo-pyridinone scaffold which retained fXa potency. The novel bicyclic scaffold preserved all binding interactions observed with the monocyclic counterpart and importantly the carboxamido moiety was integrated within the scaffold making it less susceptible to hydrolysis. These efforts led to the identification of 1-[3-aminobenzisoxazol-5'-yl]-3-trifluoromethyl-6-[2'-(3-(R)-hydroxy-N-pyrrolidinyl)methyl-[1,1']-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one 6f (BMS-740808), a highly potent (fXa Ki=30 pM) with a rapid onset of inhibition (2.7x10(7) M-1 s-1) in vitro, selective (>1000-fold over other proteases), efficacious in the AVShunt thrombosis model, and orally bioavailable inhibitor of blood coagulation factor Xa.
