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.
Woolford AJ, Day PJ, Beneton V, Berdini V, Coyle JE, Dudit Y, Grondin P, Huet P, Lee LY, Manas ES, McMenamin RL, Murray CW, Page LW, Patel VK, Potvain F, Rich SJ, Sang Y, Somers DO, Trottet L, Wan Z, Zhang X (2016) Fragment-Based Approach to the Development of an Orally Bioavailable Lactam Inhibitor of Lipoprotein-Associated Phospholipase A2 (Lp-PLA2) Journal of Medicinal Chemistry59: 10738-10749
Woolford AJ, Day PJ, Beneton V, Berdini V, Coyle JE, Dudit Y, Grondin P, Huet P, Lee LY, Manas ES, McMenamin RL, Murray CW, Page LW, Patel VK, Potvain F, Rich SJ, Sang Y, Somers DO, Trottet L, Wan Z, Zhang X (2016) Journal of Medicinal Chemistry59: 10738-10749
