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为识别新型高强度Keap1-Nrf2蛋白-蛋白相互作用抑制剂的优化努力

Kazuki Otake¹, Yoshinori Hara¹, Minoru Ubukata¹

¹Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.

Journal of medicinal chemistry

|February 26, 2024

概括

研究人员优化了一个Keap1-Nrf2蛋白质-蛋白质相互作用 (PPI) 抑制剂,产生化合物22和33. 这些新的抑制剂显示出改善的体内活性和药理动力学特征,使它们成为有前途的化学探针.

科学领域:

药用化学医学化学
药理学药理学是指药理学的学科.
生物化学生物化学

背景情况:

优化蛋白质-蛋白质相互作用 (PPI) 抑制剂的高活性和有利性质是具有挑战性的.
以前发现的一种Keap1-Nrf2 PPI 抑制剂 (化合物8) 在体内表现出中度活性.
进一步优化PPI抑制剂对于治疗开发至关重要.

研究的目的:

优化一种新的Keap1-Nrf2 PPI抑制剂,以提高功效和药理动力学特性.
通过针对特定的热点和水分子来探索结构-活动关系.
确定有前途的化学探测器,用于进一步研究Keap1-Nrf2路径调制.

主要方法:

基于结构的药物设计,针对高能水分子和Ser602.
以干效率 (LE) 为指导的化学空间的探索.
对药物动力学 (PK) 概况的评估,包括溶解性,代谢稳定性和膜透性.
在老鼠模型中的体内疗效研究.

主要成果:

确定了两个新的Keap1-Nrf2 PPI 抑制剂,化合物22和33.
获得了改善的水溶性,代谢稳定性和膜透性.
与原始化合物相比,在体内表现出更强大的活体活性.
化合物22和33表现出有利的药理动力学特征.

结论:

优化的抑制剂 (22和33) 与最初的化合物相比,代表了显著的进步.
针对特定的热点和采用LE引导优化是PPI抑制剂开发的有效策略.
化合物22和33是研究Keap1-Nrf2通路的有希望的化学探针.

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