The development of novel C-2, C-8, and N-9 trisubstituted purines as inhibitors of TNF-alpha production

  • Bioorg Med Chem Lett. 2006 Aug 15;16(16):4360-5. doi: 10.1016/j.bmcl.2006.05.050.
Mark Sabat  1 ,  John C Vanrens ,  Michael P Clark ,  Todd A Brugel ,  Jennifer Maier ,  Roger G Bookland ,  Matthew J Laufersweiler ,  Steven K Laughlin ,  Adam Golebiowski ,  Biswanath De ,  Lily C Hsieh ,  Richard L Walter ,  Marlene J Mekel ,  Michael J Janusz
Affiliations
  • 1. Procter and Gamble Pharmaceuticals, Health Care Research Center, Mason, OH 45040, USA. [email protected]
PMID: 16750367 DOI: 10.1016/j.bmcl.2006.05.050
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).