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
  • 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.

Products