RESUMO
A series of biaryl pyrazole and imidazole Liver X Receptor (LXR) partial agonists has been synthesized displaying LXRß selectivity. The LXRß selective partial agonist 18 was identified with potent induction of ATP binding transporters ABCA1 and ABCG1 in human whole blood (EC50=1.2µM, 55% efficacy). In mice 18 displayed peripheral induction of ABCA1 at 3 and 10mpk doses with no significant elevation of plasma or hepatic triglycerides at these doses, showing an improved profile compared to a full pan-agonist.
Assuntos
Transportador 1 de Cassete de Ligação de ATP/sangue , Imidazóis/farmacologia , Fígado/efeitos dos fármacos , Receptores Nucleares Órfãos/agonistas , Pirazóis/farmacologia , Sulfonas/farmacologia , Animais , Agonismo Parcial de Drogas , Humanos , Imidazóis/química , Imidazóis/farmacocinética , Fígado/metabolismo , Receptores X do Fígado , Camundongos , Modelos Moleculares , Estrutura Molecular , Plasma/química , Pirazóis/química , Pirazóis/farmacocinética , Relação Estrutura-Atividade , Sulfonas/química , Sulfonas/farmacocinética , Distribuição Tecidual , Triglicerídeos/metabolismoRESUMO
Azepino[4,5-b]indoles have been identified as potent agonists of the farnesoid X receptor (FXR). In vitro and in vivo optimization has led to the discovery of 6m (XL335, WAY-362450) as a potent, selective, and orally bioavailable FXR agonist (EC(50) = 4 nM, Eff = 149%). Oral administration of 6m to LDLR(-/-) mice results in lowering of cholesterol and triglycerides. Chronic administration in an atherosclerosis model results in significant reduction in aortic arch lesions.