发现CRN04894:一种新的强有力的选择性MC2R对手
Sun Hee Kim1, Sangdon Han1, Jian Zhao1
1Crinetics Pharmaceuticals, Inc., 6055 Lusk Blvd., San Diego, California 92121, United States.
ACS medicinal chemistry letters
|April 17, 2024
概括
研究人员开发了一种新药,17h (CRN04894) 是一种强大的MC2R抗剂. 这种药物有效地降低了老鼠的压力激素水平,现在正在针对上腺疾病进行人类临床试验.
科学领域:
- 内分泌学和药理学 在内分泌学和药理学
- 药物发现和开发 药物发现和开发
背景情况:
- 黑色皮质素2型受体 (MC2R) 在调节上腺类固醇生成中起着至关重要的作用.
- 对ACTH依赖性疾病的现有治疗方法往往具有显著的副作用.
- 选择性MC2R抗剂的开发是一个治疗目标.
研究的目的:
- 发现和描述新的,非类MC2R对手.
- 在临床前模型中评估化合物的疗效.
- 评估该化合物治疗依赖ACTH的疾病的潜力.
主要方法:
- 已知黑色皮质素4型受体 (MC4R) 配体的修改,以识别MC2R对手.
- 结构-活性关系 (SAR) 研究以优化功效和选择性.
- 在鼠标模型中进行的ACTH刺激的皮质分泌的体内研究.
- 药物特性评估和进入第一阶段临床试验的进展.
主要成果:
- 发现了一种新型的非类MC2R抗剂.
- 鉴定化合物17h (CRN04894) 作为一种高强度和亚型选择性MC2R抗剂.
- 在大鼠17h (≥3 mg/kg) 之前,证明了剂量依赖于ACTH刺激的皮质分泌的抑制.
- 17h的进展到人类临床试验的第一阶段.
结论:
- 化合物17h (CRN04894) 是一流的MC2R抗剂,具有前临床疗效.
- 17h表现出有利的药物特性,支持其临床发展.
- CRN04894具有治疗ACTH依赖性疾病的潜力,如先天性上腺增生和库辛病.
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