title: Fragment-Based Approach to the Development of an Orally Bioavailable Lactam Inhibitor of Lipoprotein-Associated Phospholipase A2 (Lp-PLA2).
abstract: Lp-PLA2has 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-PLA2inhibitors was generated with low lipophilicity and a promising pharmacokinetic profile.
authors.affiliation: Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom.
authors.forename: Alison J-A
authors.initials: AJ
authors.lastname: Woolford
authors.affiliation: Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Day
authors.affiliation: Centre de Recherches Francois Hyafil, GlaxoSmithKline , 25-27 Avenue du Québec, Les Ulis, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Bénéton
authors.affiliation: Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom.
authors.forename: Valerio
authors.initials: V
authors.lastname: Berdini
authors.affiliation: Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom.
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Coyle
authors.affiliation: Centre de Recherches Francois Hyafil, GlaxoSmithKline , 25-27 Avenue du Québec, Les Ulis, France.
authors.forename: Yann
authors.initials: Y
authors.lastname: Dudit
authors.affiliation: Centre de Recherches Francois Hyafil, GlaxoSmithKline , 25-27 Avenue du Québec, Les Ulis, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Grondin
authors.affiliation: Centre de Recherches Francois Hyafil, GlaxoSmithKline , 25-27 Avenue du Québec, Les Ulis, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Huet
authors.affiliation: Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom.
authors.forename: Lydia Y W
authors.initials: LY
authors.lastname: Lee
authors.affiliation: GlaxoSmithKline , 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States.
authors.forename: Eric S
authors.initials: ES
authors.lastname: Manas
authors.affiliation: Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom.
authors.forename: Rachel L
authors.initials: RL
authors.lastname: McMenamin
authors.affiliation: Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom.
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Murray
authors.affiliation: Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom.
authors.forename: Lee W
authors.initials: LW
authors.lastname: Page
authors.affiliation: GlaxoSmithKline , Gunnels Wood Road, Stevenage SG1 2NY, United Kingdom.
authors.forename: Vipulkumar K
authors.initials: VK
authors.lastname: Patel
authors.affiliation: Centre de Recherches Francois Hyafil, GlaxoSmithKline , 25-27 Avenue du Québec, Les Ulis, France.
authors.forename: Florent
authors.initials: F
authors.lastname: Potvain
authors.affiliation: Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom.
authors.forename: Sharna J
authors.initials: SJ
authors.lastname: Rich
authors.affiliation: Neurodegeneration DPU, GlaxoSmithKline , 898 Halei Road, Zhangjiang Hi-Tech Park, Pudong, Shanghai 201203, China.
authors.forename: Yingxia
authors.initials: Y
authors.lastname: Sang
authors.affiliation: GlaxoSmithKline , Gunnels Wood Road, Stevenage SG1 2NY, United Kingdom.
authors.forename: Don O
authors.initials: DO
authors.lastname: Somers
authors.affiliation: Centre de Recherches Francois Hyafil, GlaxoSmithKline , 25-27 Avenue du Québec, Les Ulis, France.
authors.forename: Lionel
authors.initials: L
authors.lastname: Trottet
authors.affiliation: Neurodegeneration DPU, GlaxoSmithKline , 898 Halei Road, Zhangjiang Hi-Tech Park, Pudong, Shanghai 201203, China.
authors.forename: Zehong
authors.initials: Z
authors.lastname: Wan
authors.affiliation: Neurodegeneration DPU, GlaxoSmithKline , 898 Halei Road, Zhangjiang Hi-Tech Park, Pudong, Shanghai 201203, China.
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Zhang
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D018360:Crystallography, X-Ray; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007769:Lactams / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D051381:Rats; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
chemical_list: D004791:Enzyme Inhibitors; D007769:Lactams; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; C526684:PLA2G7 protein, human