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Fragment-Based Approach to the Development of an Orally Bioavailable Lactam Inhibitor of Lipoprotein-Associated Phospholipase A2 (Lp-PLA2)

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posted on 10.11.2016, 00:00 by 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
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.