Journal of Medicinal Chemistry p. 10738 - 10749 (2016)
Update date:2022-08-22
Topics:
Woolford, Alison J.-A.
Day, Philip J.
Bénéton, Véronique
Berdini, Valerio
Coyle, Joseph E.
Dudit, Yann
Grondin, Pascal
Huet, Pascal
Lee, Lydia Y. W.
Manas, Eric S.
McMenamin, Rachel L.
Murray, Christopher W.
Page, Lee W.
Patel, Vipulkumar K.
Potvain, Florent
Rich, Sharna J.
Sang, Yingxia
Somers, Don O.
Trottet, Lionel
Wan, Zehong
Zhang, Xiaomin
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.
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