title: 3-amino-7-phthalazinylbenzoisoxazoles as a novel class of potent, selective, and orally available inhibitors of p38alpha mitogen-activated protein kinase.
abstract: The p38 mitogen-activated protein kinase (MAPK) 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, osteoporosis, and many other diseases where aberrant cytokine signaling is the driver of disease. Herein, we describe a novel class of 3-amino-7-phthalazinylbenzoisoxazole-based inhibitors. With relatively low molecular weight, these compounds are highly potent in enzyme and cell-based assays, with minimal protein shift in 50% human whole blood. Compound 3c was efficacious (ED 50 = 0.05 mg/kg) in the rat collagen induced arthritis (CIA) model.
authors.affiliation: Department of Chemistry Research and Discovery, Amgen Inc., Thousand Oaks, California 91320, USA. lpettus@amgen.com
authors.forename: Liping H
authors.initials: LH
authors.lastname: Pettus
authors.forename: Shimin
authors.initials: S
authors.lastname: Xu
authors.forename: Guo-Qiang
authors.initials: GQ
authors.lastname: Cao
authors.forename: Partha P
authors.initials: PP
authors.lastname: Chakrabarti
authors.forename: Robert M
authors.initials: RM
authors.lastname: Rzasa
authors.forename: Kelvin
authors.initials: K
authors.lastname: Sham
authors.forename: Ryan P
authors.initials: RP
authors.lastname: Wurz
authors.forename: Dawei
authors.initials: D
authors.lastname: Zhang
authors.forename: Scott
authors.initials: S
authors.lastname: Middleton
authors.forename: Bradley
authors.initials: B
authors.lastname: Henkle
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: David A
authors.initials: DA
authors.lastname: Powers
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Tudor
authors.forename: Violeta
authors.initials: V
authors.lastname: Yu
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Lee
authors.forename: Rashid
authors.initials: R
authors.lastname: Syed
authors.forename: Faye
authors.initials: F
authors.lastname: Hsieh
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Tasker
mesh_terms: D000284:Administration, Oral; D000588:Amines / Q000737:chemistry*; D000818:Animals; D001168:Arthritis / Q000139:chemically induced / Q000188:drug therapy / Q000201:enzymology; D001554:Benzene / Q000737:chemistry*; D018360:Crystallography, X-Ray; D004195:Disease Models, Animal; D006801:Humans; D007555:Isoxazoles / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D010793:Phthalazines / Q000737:chemistry*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000588:Amines; D007555:Isoxazoles; D010793:Phthalazines; D047428:Protein Kinase Inhibitors; D048308:Mitogen-Activated Protein Kinase 14; D001554:Benzene