RESUMO
The discovery of a series of selective EP1 receptor antagonists based on a 1,2-diarylcyclopentene template is described. After defining the structural requirements for EP1 potency and selectivity, heterocyclic rings were incorporated to reduce logD and improve in vitro pharmacokinetic properties. The 2,6-substituted pyridines and pyridazines gave an appropriate balance of potency, in vivo pharmacokinetic properties and a low potential for inhibiting a range of CYP450 enzymes. From this series, GW848687X was shown to have an excellent profile in models of inflammatory pain and was selected as a development candidate.
Assuntos
Alprostadil/metabolismo , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/farmacologia , Ciclopentanos/síntese química , Ciclopentanos/farmacologia , Inflamação/tratamento farmacológico , Dor/tratamento farmacológico , Piridinas/síntese química , Piridinas/farmacologia , Receptores de Prostaglandina E/antagonistas & inibidores , Animais , Anti-Inflamatórios não Esteroides/farmacocinética , Disponibilidade Biológica , Sistema Enzimático do Citocromo P-450/metabolismo , Cães , Relação Dose-Resposta a Droga , Adjuvante de Freund , Meia-Vida , Inflamação/induzido quimicamente , Inflamação/complicações , Dor/etiologia , RatosRESUMO
We describe the generation of novel EP(1) receptor antagonists by investigation of thiophene isosteres. In addition, we disclose preliminary in vitro and in vivo DMPK for selected compounds.
Assuntos
Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Receptores de Prostaglandina E/antagonistas & inibidores , Animais , Técnicas In Vitro , Ratos , Receptores de Prostaglandina E Subtipo EP1RESUMO
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.