RESUMO
In an attempt to molecularly design liver X receptor (LXR) ß-selective agonists, we discovered that the combination of the 2-oxochromene moiety (head) and the imidazoline-2,4-dione moiety (tail) plays an important role in the expression potency and selectivity toward LXRß. We synthesized a series of 2-oxochromene derivatives and identified 43 as a LXRß-selective agonist that increased the HDL-C level without significantly elevating the TG level and resulted in a decreased lipid-accumulation area in the aortic arch in a high-fat-and-cholesterol-fed Bio F1B hamster. In this manuscript, we report the design, synthesis and pharmacology of these 2-oxochromene derivatives.
Assuntos
Benzopiranos/química , Cumarínicos/química , Desenho de Fármacos , Hidantoínas/química , Receptores Nucleares Órfãos/agonistas , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/metabolismo , Benzopiranos/metabolismo , Benzopiranos/farmacologia , HDL-Colesterol/sangue , Cumarínicos/metabolismo , Cumarínicos/farmacologia , Cricetinae , Dieta Hiperlipídica , Hidantoínas/metabolismo , Hidantoínas/farmacologia , Imidazolinas/química , Receptores X do Fígado , Receptores Nucleares Órfãos/metabolismo , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
A combination of benzoxazole, phenoxyalkyl side chain, and phenoxybutyric acids was identified as a highly potent and selective human peroxisome proliferator-activated receptor alpha (PPARalpha) agonist. The synthesis, structure-activity relationship (SAR) studies, and in vivo activities of the representative compounds are described.