title: Synthesis and pharmacological characterization of a potent, orally active p38 kinase inhibitor.
abstract: Inhibitors of the MAP kinase p38 provide a novel approach for the treatment of osteoporosis, inflammatory disorders, and cancer. We have identified N-(3-tert-butyl-1-methyl-5-pyrazolyl)-N'-(4-(4-pyridinylmethyl)phenyl)urea as a potent and selective p38 kinase inhibitor in biochemical and cellular assays. This compound is orally active in two acute models of cytokine release (TNF-induced IL-6 and LPS-induced TNF) and a chronic model of arthritis (20-day murine collagen-induced arthritis).
authors.affiliation: Department of Chemistry Research, Bayer Research Center, 400 Morgan Lane, West Haven, CT 06516, USA. jacques.dumas.b@bayer.com
authors.forename: Jacques
authors.initials: J
authors.lastname: Dumas
authors.forename: Holia
authors.initials: H
authors.lastname: Hatoum-Mokdad
authors.forename: Robert N
authors.initials: RN
authors.lastname: Sibley
authors.forename: Roger A
authors.initials: RA
authors.lastname: Smith
authors.forename: William J
authors.initials: WJ
authors.lastname: Scott
authors.forename: Uday
authors.initials: U
authors.lastname: Khire
authors.forename: Wendy
authors.initials: W
authors.lastname: Lee
authors.forename: Jill
authors.initials: J
authors.lastname: Wood
authors.forename: Donald
authors.initials: D
authors.lastname: Wolanin
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Cooley
authors.forename: Donald
authors.initials: D
authors.lastname: Bankston
authors.forename: Aniko M
authors.initials: AM
authors.lastname: Redman
authors.forename: Robert
authors.initials: R
authors.lastname: Schoenleber
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Caringal
authors.forename: David
authors.initials: D
authors.lastname: Gunn
authors.forename: Romulo
authors.initials: R
authors.lastname: Romero
authors.forename: Martin
authors.initials: M
authors.lastname: Osterhout
authors.forename: Holger
authors.initials: H
authors.lastname: Paulsen
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Housley
authors.forename: Scott M
authors.initials: SM
authors.lastname: Wilhelm
authors.forename: John
authors.initials: J
authors.lastname: Pirro
authors.forename: Du-Shieng
authors.initials: DS
authors.lastname: Chien
authors.forename: Gerald E
authors.initials: GE
authors.lastname: Ranges
authors.forename: Alka
authors.initials: A
authors.lastname: Shrikhande
authors.forename: Andrew
authors.initials: A
authors.lastname: Muzsi
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Bortolon
authors.forename: Jean
authors.initials: J
authors.lastname: Wakefield
authors.forename: Cynthia
authors.initials: C
authors.lastname: Gianpaolo Ostravage
authors.forename: Ajay
authors.initials: A
authors.lastname: Bhargava
authors.forename: Thuy
authors.initials: T
authors.lastname: Chau
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001168:Arthritis / Q000188:drug therapy; D016207:Cytokines / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D014508:Urea / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D016207:Cytokines; D004791:Enzyme Inhibitors; C468807:N-(3-tert-butyl-1-methyl-5-pyrazolyl)-N'-(4-(4-pyridinylmethyl)phenyl)urea; D014508:Urea; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases