发现口服AMP激活蛋白激酶激活剂用于治疗高脂血症
Mingchao Wang1, Zunsheng Han1, Baoyan Fan1
1State Key Laboratory for Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Xian Nong Tan Street 1, Xicheng District, Beijing 100050, China.
Journal of medicinal chemistry
|May 13, 2024
概括
一种新型化合物V1有效地激活AMP激活蛋白激酶 (AMPK) 以降低胆固醇. 这种强大的AMPK激活剂在动物模型中表现出显著的降脂效应,并在人类中完成了1期临床试验.
科学领域:
- 生物化学 生物化学
- 药理学 药理学是指药理学的学科.
- 代谢疾病 代谢疾病
背景情况:
- AMP激活蛋白激酶 (AMPK) 激活是超脂血症的潜在治疗策略.
- 科尔迪塞宾和N6-(2-基乙烯) 腺 (HEA) 作为开发新AMPK激活剂的化合物.
研究的目的:
- 设计,合成和评估用于AMPK激活和降脂效应的基于腺素的新型衍生物.
- 确定一种强大的AMPK激活剂,对高脂血症有潜在的临床应用.
主要方法:
- 基于腺的衍生物的设计和合成.
- 在体外评估AMPK激活和分子对接研究.
- 在多个动物模型 (小鼠,仓鼠,子) 和人类第一阶段临床试验中进行体内降脂疗效评估.
- RNA测序以分析肝脏中的基因表达变化.
主要成果:
- 化合物V1被确定为一种强大的AMPK激活剂,具有显著的降脂效应.
- 分子对接和循环二元化证实V1与AMPK的γ亚单元结合.
- 在各种动物模型中,V1显著降低了血清低密度脂蛋白胆固醇.
- 第1期临床试验显示V1增加了人类红细胞中的AMPK激活.
- 通过AMPK激活,V1降低了与亡,脂质代谢,ER压力和肝脏炎症相关的基因.
结论:
- V1是一种强大的AMPK激活剂,在临床前和早期临床研究中证明了降脂功效.
- V1代表了管理高脂血症的有希望的治疗候选者.
- 作用机制涉及与AMPK γ亚单元的结合,导致下游基因表达调节.
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