3-amino-7-phthalazinylbenzoisoxazoles as a novel class of potent, selective, and orally available inhibitors of p38alpha mitogen-activated protein kinase.
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.
Pettus
Liping H
LH
Department of Chemistry Research and Discovery, Amgen Inc., Thousand Oaks, California 91320, USA. lpettus@amgen.com
Xu
Shimin
S
Cao
Guo-Qiang
GQ
Chakrabarti
Partha P
PP
Rzasa
Robert M
RM
Sham
Kelvin
K
Wurz
Ryan P
RP
Zhang
Dawei
D
Middleton
Scott
S
Henkle
Bradley
B
Plant
Matthew H
MH
Saris
Christiaan J M
CJ
Sherman
Lisa
L
Wong
Lu Min
LM
Powers
David A
DA
Tudor
Yanyan
Y
Yu
Violeta
V
Lee
Matthew R
MR
Syed
Rashid
R
Hsieh
Faye
F
Tasker
Andrew S
AS
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
D000588:Amines; D007555:Isoxazoles; D010793:Phthalazines; D047428:Protein Kinase Inhibitors; D048308:Mitogen-Activated Protein Kinase 14; D001554:Benzene