RESUMO
[reaction: see text] In this, the first of two letters, we outline the use of the pyrrolidine-5,5-trans-lactam template to design small, neutral, mechanism-based inhibitors of hepatitis C NS3/4A protease. The hitherto unreported reaction of the acyl iminium ion precursor 4 with dialkyl-substituted silyl ketene acetals (e.g., 8b) is described. Compound 12b, with a spirocyclobutyl P1 substituent and a cyclopropylacyl substituent on the lactam nitrogen, has a k(obs)/I of 400 M(-)(1) s(-)(1) and demonstrates activity in a replicon cell-based surrogate HCV assay.
Assuntos
Hepacivirus/enzimologia , Lactamas/síntese química , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Pirrolidinas/síntese química , Serina Endopeptidases/metabolismo , Proteínas não Estruturais Virais/antagonistas & inibidores , Linhagem Celular , Desenho de Fármacos , Estabilidade de Medicamentos , Hepacivirus/efeitos dos fármacos , Humanos , Lactamas/química , Estrutura Molecular , Inibidores de Proteases/química , Pirrolidinas/química , Proteínas não Estruturais Virais/metabolismoRESUMO
[reaction: see text] In this, the second of two Letters, the optimization of the pyrrolidine-5,5-trans-lactam template (exemplified by 1a) as a mechanism-based inhibitor of hepatitis C NS3/4A protease is described. "Right Box" analysis of cassette dosing screening pharmacokinetic data was used to rapidly categorize the compounds. GW0014 (compound 4d) emerged as the compound displaying an optimal balance of biochemical and replicon potency, along with low i.v. clearance in the dog.
Assuntos
Lactamas/química , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacocinética , Pirrolidinas/química , Proteínas não Estruturais Virais/antagonistas & inibidores , Concentração Inibidora 50 , Estrutura Molecular , Inibidores de Proteases/química , Proteínas não Estruturais Virais/metabolismoRESUMO
[reaction: see text] In this, the second of two letters, we describe the elaboration of the pyrrolidine-5,5-trans-lactam template to delineate the requirements for optimal substitution of the pyrrolidine and lactam nitrogen atoms. Central to the strategy is the use of rapid iterative synthesis in conjunction with X-ray crystal structure determination of ligand-protein complexes.
Assuntos
Desenho de Fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/síntese química , Lactamas/síntese química , Pirrolidinas/síntese química , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/química , Linhagem Celular , Cristalografia por Raios X , Inibidores Enzimáticos/farmacologia , Hepacivirus/efeitos dos fármacos , Hepacivirus/enzimologia , Concentração Inibidora 50 , Lactamas/química , Lactamas/farmacologia , Modelos Moleculares , Estrutura Molecular , Conformação Proteica , Pirrolidinas/química , Pirrolidinas/farmacologia , Proteínas não Estruturais Virais/metabolismoRESUMO
The pyrrolidine-5,5-trans-lactam template was used to design small, neutral, mechanism-based inhibitors of hepatitis C NS3/4A protease displaying potent activity in the replicon cell-based assay. The activity of this series is not dependent upon its chemical reactivity and molecules have been synthesised which combine enhanced biochemical potency with improved plasma stability. Promising initial pharmacokinetic data indicating the potential for further optimisation of this series into low molecular weight, drug-like inhibitors is presented.