RESUMO
The Hedgehog (Hh-) signalling pathway is a key developmental pathway and there is a growing body of evidence showing that this pathway is aberrantly reactivated in a number of human tumors. Novel agents capable of inhibiting this pathway are sought, and an entirely novel series of smoothened (Smo) antagonists capable of inhibiting the pathway have been identified through uHTS screening. Extensive exploration of the scaffold identified the key functionalities necessary for potency, enabling potent nanomolar Smo antagonists like 91 and 94 to be developed. Optimization resulted in the most advanced compounds displaying low serum shift, clean off-targets profile, and moderate clearance in both rats and dogs. These compounds are valuable tools with which to probe the biology of the Hh-pathway.
Assuntos
Proteínas Hedgehog/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Ureia/farmacologia , Animais , Cães , Relação Dose-Resposta a Droga , Proteínas Hedgehog/metabolismo , Humanos , Microssomos/efeitos dos fármacos , Microssomos/metabolismo , Estrutura Molecular , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Ureia/análogos & derivados , Ureia/químicaRESUMO
Herein we describe the discovery of a novel series of pyrrolo[1,2-a]pyrazin-1(2H)-one PARP inhibitors. Optimization led to compounds that display excellent PARP-1 enzyme potency and inhibit the proliferation of BRCA deficient cells in the low double-digit nanomolar range showing excellent selectivity over BRCA proficient cancer cells.