黑素皮质素
敌手
皮质酮
医学
药理学
促肾上腺皮质激素
内分泌学
效力
内科学
激素
受体
体外
化学
生物化学
作者
S H Kim,Sangdon Han,Jian Zhao,Shimiao Wang,Ana Karin Kusnetzow,Greg J. Reinhart,Melissa Fowler,Stacy Markison,Michael Johns,Rosa Luo,R. Scott Struthers,Yunfei Zhu,Stephen F. Betz
标识
DOI:10.1021/acsmedchemlett.3c00514
摘要
A novel class of nonpeptide melanocortin type 2 receptor (MC2R) antagonists was discovered through modification of known nonpeptide MC4R ligands. Structure–activity relationship (SAR) studies led to the discovery of 17h (CRN04894), a highly potent and subtype-selective first-in-class MC2R antagonist, which demonstrated remarkable efficacy in a rat model of adrenocorticotrophic hormone (ACTH)-stimulated corticosterone secretion. Oral administration of 17h suppressed ACTH-stimulated corticosterone secretion in a dose-dependent manner at doses ≥3 mg/kg. With its satisfactory pharmaceutical properties, 17h was advanced to Phase 1 human clinical trials in healthy volunteers with the goal of moving into patient trials to evaluate CRN04894 for the treatment of ACTH-dependent diseases, including congenital adrenal hyperplasia (CAH) and Cushing's disease (CD).
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