Discovery of CRN04894: A Novel Potent Selective MC2R Antagonist
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
Abstract
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).