Grondin P

References (2)

Title : Fragment-Based Approach to the Development of an Orally Bioavailable Lactam Inhibitor of Lipoprotein-Associated Phospholipase A2 (Lp-PLA2) - Woolford_2016_J.Med.Chem_59_10738
Author(s) : 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
Ref : Journal of Medicinal Chemistry , 59 :10738 , 2016
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.
ESTHER : Woolford_2016_J.Med.Chem_59_10738
PubMedSearch : Woolford_2016_J.Med.Chem_59_10738
PubMedID: 27933945
Gene_locus related to this paper: human-PLA2G7

Title : Exploitation of a Novel Binding Pocket in Human Lipoprotein-Associated Phospholipase A2 (Lp-PLA2) Discovered through X-ray Fragment Screening - Woolford_2016_J.Med.Chem_59_5356
Author(s) : Woolford AJ , Pero JE , Aravapalli S , Berdini V , Coyle JE , Day PJ , Dodson AM , Grondin P , Holding FP , Lee LY , Li P , Manas ES , Marino J, Jr. , Martin AC , McCleland BW , McMenamin RL , Murray CW , Neipp CE , Page LW , Patel VK , Potvain F , Rich S , Rivero RA , Smith K , Somers DO , Trottet L , Velagaleti R , Williams G , Xie R
Ref : Journal of Medicinal Chemistry , 59 :5356 , 2016
Abstract : Elevated levels of human lipoprotein-associated phospholipase A2 (Lp-PLA2) are associated with cardiovascular disease and dementia. A fragment screen was conducted against Lp-PLA2 in order to identify novel inhibitors. Multiple fragment hits were observed in different regions of the active site, including some hits that bound in a pocket created by movement of a protein side chain (approximately 13 A from the catalytic residue Ser273). Using structure guided design, we optimized a fragment that bound in this pocket to generate a novel low nanomolar chemotype, which did not interact with the catalytic residues.
ESTHER : Woolford_2016_J.Med.Chem_59_5356
PubMedSearch : Woolford_2016_J.Med.Chem_59_5356
PubMedID: 27167608
Gene_locus related to this paper: human-PLA2G7