title: The development of novel C-2, C-8, and N-9 trisubstituted purines as inhibitors of TNF-alpha production.
abstract: A series of C-2, C-8, and N-9 trisubstituted purine based inhibitors of TNF-alpha production are described. The most potent analogs showed low nanomolar activity against LPS-induced TNF-alpha production in a THP-1 cell based assay. The SAR of the series was optimized with the aid of X-ray co-crystal structures of these inhibitors bound with mutated p38 (mp38).
authors.affiliation: Procter and Gamble Pharmaceuticals, Health Care Research Center, Mason, OH 45040, USA. sabat.mp@pg.com
authors.forename: Mark
authors.initials: M
authors.lastname: Sabat
authors.forename: John C
authors.initials: JC
authors.lastname: Vanrens
authors.forename: Michael P
authors.initials: MP
authors.lastname: Clark
authors.forename: Todd A
authors.initials: TA
authors.lastname: Brugel
authors.forename: Jennifer
authors.initials: J
authors.lastname: Maier
authors.forename: Roger G
authors.initials: RG
authors.lastname: Bookland
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Laufersweiler
authors.forename: Steven K
authors.initials: SK
authors.lastname: Laughlin
authors.forename: Adam
authors.initials: A
authors.lastname: Golebiowski
authors.forename: Biswanath
authors.initials: B
authors.lastname: De
authors.forename: Lily C
authors.initials: LC
authors.lastname: Hsieh
authors.forename: Richard L
authors.initials: RL
authors.lastname: Walter
authors.forename: Marlene J
authors.initials: MJ
authors.lastname: Mekel
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Janusz
mesh_terms: D002460:Cell Line; D002626:Chemistry, Pharmaceutical; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D008070:Lipopolysaccharides / Q000737:chemistry; D008956:Models, Chemical; D008958:Models, Molecular; D011687:Purines / Q000737:chemistry*; D014409:Tumor Necrosis Factor-alpha / Q000737:chemistry*; D048051:p38 Mitogen-Activated Protein Kinases / Q000737:chemistry / Q000235:genetics
chemical_list: D008070:Lipopolysaccharides; D011687:Purines; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases