Discovery of CRN04894: A Novel Potent Selective MC2R Antagonist

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL ACS Medicinal Chemistry Letters Pub Date : 2024-03-19 DOI:10.1021/acsmedchemlett.3c00514

Sun Hee Kim*, Sangdon Han, Jian Zhao, Shimiao Wang, Ana Karin Kusnetzow, Greg Reinhart, Melissa A. Fowler, Stacy Markison, Michael Johns, Rosa Luo, R. Scott Struthers, Yunfei Zhu and Stephen F. Betz,

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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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发现 CRN04894：一种新型强效选择性 MC2R 拮抗剂

通过对已知的非肽类 MC4R 配体进行修饰，发现了一类新型非肽类黑色素皮质素 2 型受体（MC2R）拮抗剂。结构-活性关系（SAR）研究发现了 17h（CRN04894），它是一种高效力和亚型选择性的第一类 MC2R 拮抗剂，在肾上腺皮质激素（ACTH）刺激皮质酮分泌的大鼠模型中表现出显著疗效。在剂量≥3 毫克/千克时，口服 17h 能以剂量依赖的方式抑制促肾上腺皮质激素刺激的皮质酮分泌。由于 17h 具有令人满意的药理特性，因此已被推进到在健康志愿者中进行的 1 期人体临床试验，目标是进入患者试验，以评估 CRN04894 用于治疗 ACTH 依赖性疾病（包括先天性肾上腺皮质增生症（CAH）和库欣病（CD））的疗效。

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.