title: Discovery and evaluation of 7-alkyl-1,5-bis-aryl-pyrazolopyridinones as highly potent, selective, and orally efficacious inhibitors of p38alpha mitogen-activated protein kinase.
abstract: The p38alpha mitogen-activated protein (MAP) kinase is a central signaling molecule in many proinflammatory pathways, regulating the cellular response to a multitude of external stimuli including heat, ultraviolet radiation, osmotic shock, and a variety of cytokines especially interleukin-1beta and tumor necrosis factor alpha. Thus, inhibitors of this enzyme are postulated to have significant therapeutic potential for the treatment of rheumatoid arthritis, inflammatory bowel disease, and Crohn's disease, as well as other diseases where aberrant cytokine signaling is the driver of disease. In this communication, we describe a novel class of 7-alkyl-1,5-bis-aryl-pyrazolopyridinone-based p38alpha inhibitors. In particular, compound 3f is highly potent in the enzyme and cell-based assays, selective in an Ambit kinase screen, and efficacious (ED(50) < or = 0.01 mg/kg) in the rat collagen induced arthritis (CIA) model.
authors.affiliation: Departments of Chemistry Research and Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA. lpettus@amgen.com
authors.forename: Liping H
authors.initials: LH
authors.lastname: Pettus
authors.forename: Ryan P
authors.initials: RP
authors.lastname: Wurz
authors.forename: Shimin
authors.initials: S
authors.lastname: Xu
authors.forename: Brad
authors.initials: B
authors.lastname: Herberich
authors.forename: Bradley
authors.initials: B
authors.lastname: Henkle
authors.forename: Qiurong
authors.initials: Q
authors.lastname: Liu
authors.forename: Helen J
authors.initials: HJ
authors.lastname: McBride
authors.forename: Sharon
authors.initials: S
authors.lastname: Mu
authors.forename: Matthew H
authors.initials: MH
authors.lastname: Plant
authors.forename: Christiaan J M
authors.initials: CJ
authors.lastname: Saris
authors.forename: Lisa
authors.initials: L
authors.lastname: Sherman
authors.forename: Lu Min
authors.initials: LM
authors.lastname: Wong
authors.forename: Samer
authors.initials: S
authors.lastname: Chmait
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Lee
authors.forename: Christopher
authors.initials: C
authors.lastname: Mohr
authors.forename: Faye
authors.initials: F
authors.lastname: Hsieh
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Tasker
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001168:Arthritis / Q000139:chemically induced / Q000188:drug therapy; D003094:Collagen / Q000494:pharmacology; D055808:Drug Discovery; D006801:Humans; D008297:Male; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008958:Models, Molecular; D008968:Molecular Conformation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D011728:Pyridones / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D047428:Protein Kinase Inhibitors; D011728:Pyridones; D003094:Collagen; D048308:Mitogen-Activated Protein Kinase 14