The development of monocyclic pyrazolone based cytokine synthesis inhibitors

  • Bioorg Med Chem Lett. 2005 May 2;15(9):2285-9. doi: 10.1016/j.bmcl.2005.03.007.
Adam Golebiowski  1 ,  Jennifer A Townes ,  Matthew J Laufersweiler ,  Todd A Brugel ,  Michael P Clark ,  Cynthia M Clark ,  Jane F Djung ,  Steven K Laughlin ,  Mark P Sabat ,  Roger G Bookland ,  John C VanRens ,  Biswanath De ,  Lily C Hsieh ,  Michael J Janusz ,  Richard L Walter ,  Mark E Webster ,  Marlene J Mekel
Affiliations
  • 1. Procter and Gamble Pharmaceuticals, Health Care Research Center, 8700 Mason-Montgomery Rd, Mason, OH 45040, USA. [email protected]
PMID: 15837310 DOI: 10.1016/j.bmcl.2005.03.007
Abstract

4-Aryl-5-pyrimidyl based cytokine synthesis inhibitors that contain a novel monocyclic, pyrazolone heterocyclic core are described. Many of these inhibitors showed low nanomolar activity against LPS-induced TNF-alpha production. One of the compounds (6e) was found to be efficacious in the rat iodoacetate (RIA) in vivo model of Osteoarthritis. The X-ray crystal structure of a pyrazolone inhibitor cocrystallized with mutated p38 (mp38) is presented.