RESUMO
The liver X receptors (LXR) play a key role in cholesterol homeostasis and lipid metabolism. SAR studies around tertiary-amine lead molecule 2, an LXR full agonist, revealed that steric and conformational changes to the acetic acid and propanolamine groups produce dramatic effects on agonist efficacy and potency. The new analogs possess good functional activity, demonstrating the ability to upregulate LXR target genes, as well as promote cholesterol efflux in macrophages.
Assuntos
Aminas/química , Colesterol/metabolismo , Macrófagos/efeitos dos fármacos , Receptores Nucleares Órfãos/agonistas , Aminas/síntese química , Aminas/farmacocinética , Animais , Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Humanos , Receptores X do Fígado , Macrófagos/imunologia , Camundongos , Camundongos Knockout , Receptores Nucleares Órfãos/genética , Receptores Nucleares Órfãos/metabolismo , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
The discovery, proposed binding mode, and optimization of a novel class of Rho-kinase inhibitors are presented. Appropriate substitution on the 6-position of the azabenzimidazole core provided subnanomolar enzyme potency in vitro while dramatically improving selectivity over a panel of other kinases. Pharmacokinetic data was obtained for the most potent and selective examples and one (6n) has been shown to lower blood pressure in a rat model of hypertension.
Assuntos
Anti-Hipertensivos/síntese química , Benzimidazóis/síntese química , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Oxidiazóis/síntese química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Animais , Anti-Hipertensivos/farmacocinética , Anti-Hipertensivos/farmacologia , Aorta/efeitos dos fármacos , Aorta/fisiologia , Benzimidazóis/farmacocinética , Benzimidazóis/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Técnicas In Vitro , Modelos Moleculares , Contração Muscular/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/fisiologia , Oxidiazóis/farmacocinética , Oxidiazóis/farmacologia , Ratos , Ratos Endogâmicos SHR , Relação Estrutura-Atividade , Quinases Associadas a rhoRESUMO
Rho kinase (ROCK1) mediates vascular smooth muscle contraction and is a potential target for the treatment of hypertension and related disorders. Indazole amide 3 was identified as a potent and selective ROCK1 inhibitor but possessed poor oral bioavailability. Optimization of this lead resulted in the discovery of a series of dihydropyridones, exemplified by 13, with improved pharmacokinetic parameters relative to the initial lead. Indazole substitution played a critical role in decreasing clearance and improving oral bioavailability.
