RESUMO
The discovery, of a series of 2-Cl-5-heteroaryl-benzamide antagonists of the P2X(7) receptor via parallel medicinal chemistry is described. Initial analogs suffered from poor metabolic stability and low Vd(ss). Multi parametric optimization led to identification of pyrazole 39 as a viable lead with excellent potency and oral bioavailability. Further attempts to improve the low Vd(ss) of 39 via introduction of amines led to analogs 40 and 41 which maintained the favorable pharmacology profile of 39 and improved Vd(ss) after iv dosing. But these analogs suffered from poor oral absorption, probably driven by poor permeability.
Assuntos
Benzamidas/farmacologia , Descoberta de Drogas , Antagonistas do Receptor Purinérgico P2X/síntese química , Antagonistas do Receptor Purinérgico P2X/farmacologia , Receptores Purinérgicos P2X7/metabolismo , Animais , Benzamidas/síntese química , Benzamidas/química , Técnicas de Química Sintética , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Antagonistas do Receptor Purinérgico P2X/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
High throughput screening (HTS) of our compound file provided an attractive lead compound with modest P2X(7) receptor antagonist potency and high selectivity against a panel of receptors and channels, but also with high human plasma protein binding and a predicted short half-life in humans. Multi-parameter optimization was used to address the potency, physicochemical and pharmacokinetic properties which led to potent P2X(7)R antagonists with good disposition properties. Compound 33 (CE-224,535) was advanced to clinical studies for the treatment of rheumatoid arthritis.
Assuntos
Benzamidas , Descoberta de Drogas , Antagonistas do Receptor Purinérgico P2 , Receptores Purinérgicos P2X7/metabolismo , Uracila/análogos & derivados , Administração Oral , Animais , Antirreumáticos/síntese química , Antirreumáticos/química , Antirreumáticos/farmacocinética , Antirreumáticos/farmacologia , Benzamidas/síntese química , Benzamidas/química , Benzamidas/farmacocinética , Benzamidas/farmacologia , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Ligação Proteica/efeitos dos fármacos , Antagonistas do Receptor Purinérgico P2/síntese química , Antagonistas do Receptor Purinérgico P2/química , Antagonistas do Receptor Purinérgico P2/farmacocinética , Antagonistas do Receptor Purinérgico P2/farmacologia , Ratos , Relação Estrutura-Atividade , Uracila/síntese química , Uracila/química , Uracila/farmacocinética , Uracila/farmacologiaRESUMO
The synthesis, structure-activity relationship, in vivo activity, and metabolic profile for a series of triazolopyridine-oxazole based p38 inhibitors are described. The deficiencies of the lead structure in the series, CP-808844, were overcome by changes to the C4 aryl group and the triazole side-chain culminating in the identification of several potential clinical candidates.
Assuntos
Inibidores Enzimáticos/farmacologia , Oxazóis/química , Piridinas/química , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/química , Química Farmacêutica , Desenho de Fármacos , Inibidores Enzimáticos/química , Humanos , Concentração Inibidora 50 , Cinética , Modelos Químicos , Solubilidade , Relação Estrutura-Atividade , Triazóis/químicaRESUMO
The synthesis and in vitro p38 alpha activity of a novel series of benzimidazolone inhibitors is described. The p38 alpha SAR is consistent with a mode of binding wherein the benzimidazolone carbonyl serves as the H-bond acceptor to Met109 of p38 alpha in a manner analogous to the pyridine nitrogen of prototypical pyridylimidazole p38 inhibitors. Potent p38 alpha activity comparable to that of several previously reported p38 inhibitors is observed for this novel chemotype.