title: Part 1: Structure-Activity Relationship (SAR) investigations of fused pyrazoles as potent, selective and orally available inhibitors of p38alpha mitogen-activated protein kinase.
abstract: 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.
authors: Department of Chemistry Research & Discovery, Amgen Inc, Thousand Oaks, CA 91320, USA. rwurz@amgen.com
authors: Ryan P
authors: RP
authors: Wurz
authors: Liping H
authors: LH
authors: Pettus
authors: Shimin
authors: S
authors: Xu
authors: Bradley
authors: B
authors: Henkle
authors: Lisa
authors: L
authors: Sherman
authors: Matthew
authors: M
authors: Plant
authors: Kent
authors: K
authors: Miner
authors: Helen
authors: H
authors: McBride
authors: Lu Min
authors: LM
authors: Wong
authors: Christiaan J M
authors: CJ
authors: Saris
authors: Matthew R
authors: MR
authors: Lee
authors: Samer
authors: S
authors: Chmait
authors: Christopher
authors: C
authors: Mohr
authors: Faye
authors: F
authors: Hsieh
authors: Andrew S
authors: AS
authors: Tasker
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics; D001665:Binding Sites; D002460:Cell Line; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D006801:Humans; D016209:Interleukin-8 / Q000097:blood; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics; D011720:Pyrazoles / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics; D011728:Pyridones / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D016209:Interleukin-8; D008070:Lipopolysaccharides; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011728:Pyridones; D014409:Tumor Necrosis Factor-alpha; D048308:Mitogen-Activated Protein Kinase 14