针对与年龄相关的认知衰退,首次优化了新型,强效,选择性的PDE11A4抑制剂
Shams Ul Mahmood1,2, Mariana Lozano Gonzalez1,2, Sreedhar Tummalapalli1,2
1Department of Chemistry & Biochemistry, Montclair State University, Montclair, New Jersey 07043, United States.
Journal of medicinal chemistry
|October 20, 2023
概括
在形成记忆的海马体中发现的基化酶11A4 (PDE11A4) 的抑制,可能会对抗与年龄相关的认知衰退. PDE11A4抑制剂在治疗老化中的记忆缺陷方面表现有前途.
科学领域:
- 神经科学是一个神经科学.
- 分子生物学分子生物学
- 药理学 药理学是指药理学的学科.
背景情况:
- 二酶11A4 (PDE11A4) 是一种循环核酸酶,在海马形成中独特表达,对长期记忆至关重要.
- 在人类和动物中,PDE11A4表达在衰老的海马中升高.
- PDE11A淘汰赛小鼠没有表现出与年龄相关的记忆缺陷或他的病理学.
研究的目的:
- 为潜在的治疗用途开发强效和选择性的PDE11A4抑制剂.
- 研究PDE11A4抑制对与年龄相关的认知衰退的治疗潜力.
主要方法:
- 利用基于酵母的高通量屏幕来识别最初的PDE11A4抑制剂.
- 优化化合物,以增强功效和制药特性.
- 在基于细胞的测定中评估了抑制功效和选择性.
主要成果:
- 实现了抑制剂功效的10倍以上的增加.
- 开发了选择性,细胞透的PDE11A4抑制剂.
- 在基于细胞的活性方面,确定了一种比tadalafil更强10倍的抑制剂.
结论:
- 抑制PDE11A4代表了与年龄相关的记忆力下降的可行治疗策略.
- 优化的PDE11A4抑制剂显示出显著的功效和细胞透性.
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