2. Academic Validation
  3. Discovery of CRN04894: A Novel Potent Selective MC2R Antagonist

Discovery of CRN04894: A Novel Potent Selective MC2R Antagonist

  • ACS Med Chem Lett. 2024 Mar 19;15(4):478-485. doi: 10.1021/acsmedchemlett.3c00514.
Sun Hee Kim 1,  Sangdon Han 1,  Jian Zhao 1,  Shimiao Wang 1,  Ana Karin Kusnetzow 1,  Greg Reinhart 1,  Melissa A Fowler 1,  Stacy Markison 1,  Michael Johns 1,  Rosa Luo 1,  R Scott Struthers 1,  Yunfei Zhu 1,  Stephen F Betz 1
Affiliations

Affiliation

  • 1 Crinetics Pharmaceuticals, Inc., 6055 Lusk Blvd., San Diego, California 92121, United States.
PMID: 38628803 DOI: 10.1021/acsmedchemlett.3c00514
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).

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