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

Mark Sabat; 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

doi:10.1016/j.bmcl.2006.05.050

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. Epub 2006 Jun 5.

Authors

Mark Sabat¹, 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

Affiliation

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).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Line
Chemistry, Pharmaceutical
Crystallography, X-Ray
Drug Design
Humans
Lipopolysaccharides / chemistry
Models, Chemical
Models, Molecular
Purines / chemistry*
Tumor Necrosis Factor-alpha / chemistry*
p38 Mitogen-Activated Protein Kinases / chemistry
p38 Mitogen-Activated Protein Kinases / genetics

Substances

Lipopolysaccharides
Purines
Tumor Necrosis Factor-alpha
p38 Mitogen-Activated Protein Kinases