一种强效且选择性磷酸二酯酶2A抑制剂的结构导向设计与认知前评估
Structure-Guided Design and Procognitive Assessment of a Potent and Selective Phosphodiesterase 2A Inhibitor.
作者信息
Stachel Shawn J, Berger Richard, Nomland Ashley B, Ginnetti Anthony T, Paone Daniel V, Wang Deping, Puri Vanita, Lange Henry, Drott Jason, Lu Jun, Marcus Jacob, Dwyer Michael P, Suon Sokreine, Uslaner Jason M, Smith Sean M
机构信息
Merck & Co. Inc., P.O. Box 4, West Point, Pennsylvania 19486, United States.
出版信息
ACS Med Chem Lett. 2018 Jul 26;9(8):815-820. doi: 10.1021/acsmedchemlett.8b00214. eCollection 2018 Aug 9.
Abstract
Herein we describe the development of a series of pyrazolopyrimidinone phosphodiesterase 2A (PDE2) inhibitors using structure-guided lead identification and design. The series was derived from informed chemotype replacement based on previously identified internal leads. The initially designed compound , while potent on PDE2, displayed unsatisfactory selectivity against the other PDE2 isoforms. Compound was subsequently optimized for improved PDE2 activity and isoform selectivity. Insights into the origins of PDE2 selectivity are described and verified using cocrystallography. An optimized lead, , demonstrated improved performance in both a rodent and a nonhuman primate cognition model.
摘要
在此，我们描述了一系列吡唑并嘧啶酮磷酸二酯酶2A（PDE2）抑制剂的研发过程，该过程采用了结构导向的先导化合物识别与设计方法。该系列化合物是基于先前确定的内部先导化合物，通过明智的化学类型替换而衍生出来的。最初设计的化合物虽然对PDE2具有活性，但对其他PDE2亚型的选择性却不尽人意。随后对化合物进行了优化，以提高其PDE2活性和亚型选择性。利用共结晶学对PDE2选择性的起源进行了深入研究并得到了验证。优化后的先导化合物在啮齿动物和非人类灵长类动物认知模型中均表现出了更好的性能。
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