Discovery of CRN04894: A Novel Potent Selective MC2R Antagonist.
Discovery of CRN04894: A Novel Potent Selective MC2R Antagonist.
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CRN04894 的发现：一种新型强效选择性 MC2R 拮抗剂。
DOI：
10.1021/acsmedchemlett.3c00514
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发表时间：
2024
影响因子：
4.2
通讯作者：
Betz,StephenF
中科院分区：
文献类型：
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作者：
Kim,SunHee;Han,Sangdon;Zhao,Jian;Wang,Shimiao;Kusnetzow,AnaKarin;Reinhart,Greg;Fowler,MelissaA;Markison,Stacy;Johns,Michael;Luo,Rosa;Struthers,RScott;Zhu,Yunfei;Betz,StephenF
通过对已知的非肽类黑素皮质素受体(MC2R)配体进行修饰，发现了一类新的非肽类MC2R拮抗剂。构效关系(SAR)研究发现了17h(CRN04894)，这是一种高度有效和亚型选择性的一级MC2R拮抗剂，在促肾上腺皮质激素(ACTH)刺激皮质酮分泌的大鼠模型中显示出显著的疗效。口服17h可剂量依赖性地抑制促肾上腺皮质激素刺激的皮质酮分泌，剂量为≥3 mg/kg。凭借其令人满意的药学特性，17h在健康志愿者身上进入第一阶段人体临床试验，目标是进入患者试验，以评估CRN04894用于治疗ACTH依赖性疾病，包括先天性肾上腺增生症(CAH)和库欣病(CD)。
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 of17h(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 of17hsuppressed ACTH-stimulated corticosterone secretion in a dose-dependent manner at doses ≥3 mg/kg. With its satisfactory pharmaceutical properties,17hwas 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).