The development of novel C-2, C-8, and N-9 trisubstituted purines as inhibitors of TNF-alpha production.
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).
Sabat
Mark
M
Procter and Gamble Pharmaceuticals, Health Care Research Center, Mason, OH 45040, USA. sabat.mp@pg.com
Vanrens
John C
JC
Clark
Michael P
MP
Brugel
Todd A
TA
Maier
Jennifer
J
Bookland
Roger G
RG
Laufersweiler
Matthew J
MJ
Laughlin
Steven K
SK
Golebiowski
Adam
A
De
Biswanath
B
Hsieh
Lily C
LC
Walter
Richard L
RL
Mekel
Marlene J
MJ
Janusz
Michael J
MJ
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
D008070:Lipopolysaccharides; D011687:Purines; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases