Discovery of CRN04894: A Novel Potent Selective MC2R Antagonist,ACS Medicinal Chemistry Letters

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Discovery of CRN04894: A Novel Potent Selective MC2R Antagonist
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2024-03-19 , 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

Affiliation

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).

中文翻译：

CRN04894 的发现：一种新型强效选择性 MC2R 拮抗剂

通过修饰已知的非肽 MC4R 配体，发现了一类新型非肽黑皮质素 2 型受体 (MC2R) 拮抗剂。构效关系 (SAR) 研究发现了17h (CRN04894)，这是一种高效且亚型选择性的一流 MC2R 拮抗剂，在促肾上腺皮质激素 (ACTH) 刺激的皮质酮大鼠模型中表现出显着疗效分泌。口服给药17小时，以剂量依赖性方式抑制ACTH刺激的皮质酮分泌，剂量≥3 mg/kg。凭借其令人满意的药物特性， 17h已在健康志愿者中进入1期人体临床试验，目标是进入患者试验，以评估CRN04894治疗ACTH依赖性疾病的效果，包括先天性肾上腺增生（CAH）和库欣病（CD））。

更新日期：2024-03-19

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