Discovery and Preclinical Sciences, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
J Med Chem. 2014 Mar 27;57(6):2601-10. doi: 10.1021/jm401858f. Epub 2014 Feb 26.
A novel series of spiroimidazolone-based antagonists of the human glucagon receptor (hGCGR) has been developed. Our efforts have led to compound 1, N-((2H-tetrazol-5-yl)methyl)-4-((R)-1-((5r,8R)-8-(tert-butyl)-3-(3,5-dichlorophenyl)-2-oxo-1,4-diazaspiro[4.5]dec-3-en-1-yl)-4,4-dimethylpentyl)benzamide (SCH 900822), a potent hGCGR antagonist with exceptional selectivity over the human glucagon-like peptide-1 receptor. Oral administration of 1 lowered 24 h nonfasting glucose levels in imprinting control region mice on a high fat diet with diet-induced obesity following single oral doses of 3 and 10 mg/kg. Furthermore, compound 1, when dosed orally, was found to decrease fasting blood glucose at 30 mg/kg in a streptozotocin-treated, diet-induced obesity mouse pharmacodynamic assay and blunt exogenous glucagon-stimulated glucose excursion in prediabetic mice.
我们开发了一系列新型的基于螺噁唑啉酮的人胰高血糖素受体（hGCGR）拮抗剂。我们的努力导致了化合物 1，N-((2H-四唑-5-基)甲基）-4-((R)-1-((5r,8R)-8-(叔丁基)-3-(3,5-二氯苯基）-2-氧代-1,4-二氮杂螺[4.5]癸-3-烯-1-基）-4,4-二甲基戊基）苯甲酰胺（SCH 900822），这是一种有效的 hGCGR 拮抗剂，对人胰高血糖素样肽-1 受体具有卓越的选择性。在高脂肪饮食诱导肥胖的印记控制区小鼠中，单次口服 3 和 10mg/kg 的 1 可降低 24 小时非禁食血糖水平。此外，在链脲佐菌素治疗的饮食诱导肥胖小鼠药效学试验中，化合物 1 以 30mg/kg 的剂量口服时可降低空腹血糖，并且可使糖尿病前期小鼠的外源性胰高血糖素刺激的血糖波动减弱。
