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Publication Abstract from PubMed

A novel class of fused pyrazole-derived inhibitors of p38alpha mitogen-activated protein kinase (MAPK) is disclosed. These inhibitors were evaluated for their ability to inhibit the p38alpha enzyme, the secretion of TNFalpha in a LPS-challenged THP1 cell line and TNFalpha-induced production of IL-8 in 50% human whole blood. This series was optimized through a SAR investigation to provide inhibitors with IC(50) values in the low single-digit nanomolar range in whole blood. Further investigation of their pharmacokinetic profiles led to the identification of two potent and orally bioavailable p38 inhibitors 10 m and 10 q. Inhibitor 10 m was found to be efficacious in vivo in the inhibition of TNFalpha production in LPS-stimulated Lewis rats with an ED(50) of 0.1mg/kg while 10 q was found to have an ED(50) of 0.05-0.07 mg/kg.

Part 1: Structure-Activity Relationship (SAR) investigations of fused pyrazoles as potent, selective and orally available inhibitors of p38alpha mitogen-activated protein kinase.,Wurz RP, Pettus LH, Xu S, Henkle B, Sherman L, Plant M, Miner K, McBride H, Wong LM, Saris CJ, Lee MR, Chmait S, Mohr C, Hsieh F, Tasker AS Bioorg Med Chem Lett. 2009 Aug 15;19(16):4724-8. Epub 2009 Jun 17. PMID:19574047^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.