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

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

  • J Med Chem. 2016 Dec 8;59(23):10738-10749. doi: 10.1021/acs.jmedchem.6b01427.
Alison J-A Woolford 1,  Philip J Day 1,  Véronique Bénéton 2,  Valerio Berdini 1,  Joseph E Coyle 1,  Yann Dudit 2,  Pascal Grondin 2,  Pascal Huet 2,  Lydia Y W Lee 1,  Eric S Manas 3,  Rachel L McMenamin 1,  Christopher W Murray 1,  Lee W Page 1,  Vipulkumar K Patel 4,  Florent Potvain 2,  Sharna J Rich 1,  Yingxia Sang 5,  Don O Somers 4,  Lionel Trottet 2,  Zehong Wan 5,  Xiaomin Zhang 5
Affiliations

Affiliations

  • 1 Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom.
  • 2 Centre de Recherches Francois Hyafil, GlaxoSmithKline , 25-27 Avenue du Québec, Les Ulis, France.
  • 3 GlaxoSmithKline , 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States.
  • 4 GlaxoSmithKline , Gunnels Wood Road, Stevenage SG1 2NY, United Kingdom.
  • 5 Neurodegeneration DPU, GlaxoSmithKline , 898 Halei Road, Zhangjiang Hi-Tech Park, Pudong, Shanghai 201203, China.
PMID: 27933945 DOI: 10.1021/acs.jmedchem.6b01427
Abstract

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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