The development of new bicyclic pyrazole-based cytokine synthesis inhibitors

  • Bioorg Med Chem Lett. 2004 Oct 4;14(19):4945-8. doi: 10.1016/j.bmcl.2004.07.024.
Jennifer A Townes  1 ,  Adam Golebiowski ,  Michael P Clark ,  Matthew J Laufersweiler ,  Todd A Brugel ,  Mark Sabat ,  Roger G Bookland ,  Steve K Laughlin ,  John C VanRens ,  Biswanath De ,  Lily C Hsieh ,  Susan C Xu ,  Michael J Janusz ,  Richard L Walter
Affiliations
  • 1. Procter and Gamble Pharmaceuticals, Health Care Research Center, 8700 Mason-Montgomery Rd, Mason, OH 45040, USA. [email protected]
PMID: 15341957 DOI: 10.1016/j.bmcl.2004.07.024
Abstract

4-Aryl-5-pyrimidyl-based cytokine synthesis inhibitors of TNF-alpha production, which contain a novel bicyclic pyrazole heterocyclic core, are described. Many of these inhibitors showed low nanomolar activity against LPS-induced TNF-alpha production in a THP-1 cell-based assay and against human p38 alpha MAP kinase in an isolated enzyme assay. The X-ray crystal structure of a bicyclic pyrazole inhibitor co-crystallized with mutated p38 (mp38) is presented.