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
Through the use of computational modeling, a series of pyrimidinetrione-based inhibitors of MMP-13 was designed based on a lead inhibitor identified through file screening. Incorporation of a biaryl ether moiety at the C-5 position of the pyrimidinetrione ring resulted in a dramatic enhancement of MMP-13 potency. Protein crystallography revealed that this moiety binds in the S(1)(') pocket of the enzyme. Optimization of the C-4 substituent of the terminal aromatic ring led to incorporation of selectivity versus MMP-14 (MT-1 MMP). Structure activity relationships of the biaryl ether substituent are presented as is pharmacokinetic data for a compound that meets our in vitro potency and selectivity goals.
