Fragment-Based Approach to the Development of an Orally Bioavailable Lactam Inhibitor of Lipoprotein-Associated Phospholipase A2 (Lp-PLA2)
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- 作者：Alison J.-A. Woolford ; Philip J. Day ; Véronique Bénéton ; Valerio Berdini ; Joseph E. Coyle ; Yann Dudit ; Pascal Grondin ; Pascal Huet ; Lydia Y. W. Lee ; Eric S. Manas ; Rachel L. McMenamin ; Christopher W. Murray ; Lee W. Page ; Vipulkumar K. Patel ; Florent Potvain ; Sharna J. Rich ; Yingxia Sang ; Don O. Somers ; Lionel Trottet ; Zehong Wan ; Xiaomin Zhang
- 刊名：Journal of Medicinal Chemistry
- 出版年：2016
- 出版时间：December 8, 2016
- 年：2016
- 卷：59
- 期：23
- 页码：10738-10749
- 全文大小：811K
- ISSN：1520-4804
文摘
Lp-PLA2 has been explored as a target for a number of inflammation associated diseases, including cardiovascular disease and dementia. This article describes the discovery of a new fragment derived chemotype that interacts with the active site of Lp-PLA2. The starting fragment hit was discovered through an X-ray fragment screen and showed no activity in the bioassay (IC50 > 1 mM). The fragment hit was optimized using a variety of structure-based drug design techniques, including virtual screening, fragment merging, and improvement of shape complementarity. A novel series of Lp-PLA2 inhibitors was generated with low lipophilicity and a promising pharmacokinetic profile.