RESUMEN
Herein, we describe the discovery, synthesis, and evaluation of a novel series of spiro[chromane-2,4'-piperidine] derivatives as G-protein-coupled receptor 119 agonists. Their initial design exploited the conformational restriction in the linker-to-tail moiety, which was a key concept in this study, to give lead compound 11 (EC50â¯=â¯369â¯nM, Emaxâ¯=â¯82%). An extensive structure-activity relationship study resulted in the identification of the optimized drug candidate (R)-29 (EC50â¯=â¯54â¯nM, Emaxâ¯=â¯181%). The defining structural features of the series were a terminal benzyl-type bulky substituent and a methylene linker between the sulfonyl and phenyl groups, both of which were in the head moiety as well as the spiro-type scaffold in the linker-to-tail moiety. An in vivo oral glucose-tolerance test using C57BL/6N mice showed that (R)-29 reduced glucose excursion at a dose of 3â¯mg/kg in a dose-dependent manner.
Asunto(s)
Cromanos/farmacología , Proteínas de Unión al GTP/metabolismo , Piperidinas/metabolismo , Administración Oral , Disponibilidad Biológica , Piperidinas/farmacologíaRESUMEN
We describe the discovery and optimization of a novel series of furo[3,2-d]pyrimidines as G protein-coupled receptor 119 agonists. Agonistic activity of 4 (EC50=129nM) was improved by replacing the intramolecular hydrogen bond between the fluorine atom and the aniline hydrogen in the head moiety with a covalent C-C bond to enhance conformational restriction, which consequently gave a lead compound 12 (EC50=53nM). Optimized compound 26, which was identified by the further optimization of 12, exhibited potent activity (EC50=42nM) with improved clearance in liver microsomes and induced a 33% reduction in blood glucose area under the curve at a dose of 10mg/kg in an oral glucose tolerance test in C57BL/6N mice.
Asunto(s)
Hipoglucemiantes/química , Hipoglucemiantes/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Receptores Acoplados a Proteínas G/agonistas , Administración Oral , Animales , Glucemia/análisis , Glucemia/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Prueba de Tolerancia a la Glucosa , Humanos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/farmacocinética , Ratones Endogámicos C57BL , Pirimidinas/administración & dosificación , Pirimidinas/farmacocinética , Receptores Acoplados a Proteínas G/metabolismo , Relación Estructura-ActividadRESUMEN
Our research found that the 2-hydroxyacetophenone derivative is an outstanding linker between the 1,1-bistrifluoromethylcarbinol moiety and the imidazolidine-2,4-dione moiety to enhance the potency and ß-selectivity of liver X receptor (LXR) agonist in our head-to-tail molecular design. The incorporation of this linker is 20-fold more potent than our previous compound (2) for LXR ß agonistic activity (EC50) in a GAL-4 luciferase assay. Furthermore, we also identified 5-[5-(1-methylethoxy)pyridyl-2-yl]-5-methylimidazoline-2,4-dione (54), which lowers the lipophilicity of 2-hydroxyacetophenone derivative. We revealed that a combination of our newly developed linker and hydantoin (54) plays a pivotal role in improving the potency and selectivity of LXRß. The optically separated (-)-56 increases high-density lipoprotein cholesterol levels without elevating plasma triglyceride levels and results in a decrease of the lipid accumulation area in the aortic arch in a high-fat- and cholesterol-fed low-density lipoprotein receptor knock-out mice. In this manuscript, we report that (-)-56 is a highly potent and ß-selective LXR agonist for use in the treatment of atherosclerosis.