KR-003048, a potent, orally active inhibitor of p38 mitogen-activated protein kinase.
The tumor necrosis factor-alpha (TNF-alpha) cytokine, secreted by activated monocytes/macrophages and T lymphocytes, is implicated in several diseases, including rheumatoid arthritis, chronic obstructive pulmonary disease, inflammatory bowel disease, and osteoporosis. Monocyte/macrophage production of TNF-alpha is largely driven by p38alpha mitogen-activated protein kinase (MAP kinase), an intracellular soluble serine-threonine kinase. p38alpha MAP kinase is activated by growth factors, cellular stresses, and cytokines such as TNF-alpha and interleukin-l (IL-I). The primary contribution of p38alpha activation to excess TNF-alpha in settings of both chronic and acute inflammation has instigated efforts to find inhibitors of this enzyme as possible therapies for associated disease states. Analogue design, synthesis, and structure-activity studies led to the identification of 5-tert-butyl-N-cyclopropyl-2-methoxy-3-{2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-2-oxo-acetylamino}-benzamide (KR-003048) as a potent inhibitor of the p38 MAP kinase signaling pathway in vitro and in vivo. The inhibition in vitro of human p38alpha enzyme activity and lipopolysaccharide (LPS)-induced p38 activation and subsequent TNF-alpha release is described. KR-00348 was demonstrated to be a potent inhibitor of inflammatory cytokine production ex vivo in rat and human whole blood, and showed good oral bioavailability. Additionally, efficacy in mouse and rat models of acute and chronic inflammation was obtained. KR-003048 possessed therapeutic activity in acute models, demonstrating substantial inhibition of carrageenan-induced paw edema and in vivo LPS-induced TNF release at 30mg/kg p.o. Collagen-induced arthritis in mice was significantly inhibited by 10 and 30mg/kg doses of KR-003048. Evidence for disease-modifying activity in this model was indicated by histological evaluation of joints.
Montalban
Antonio Garrido
AG
Drug Discovery, Kemia, Inc., San Diego, CA, United States.
Boman
Erik
E
Chang
Chau-Dung
CD
Ceide
Susana Conde
SC
Dahl
Russell
R
Dalesandro
David
D
Delaet
Nancy G J
NG
Erb
Eric
E
Ernst
Justin
J
Gibbs
Andrew
A
Kahl
Jeffrey
J
Kessler
Linda
L
Lundström
Jan
J
Miller
Stephen
S
Nakanishi
Hiroshi
H
Roberts
Edward
E
Saiah
Eddine
E
Sullivan
Robert
R
Wang
Zhijun
Z
Larson
Christopher J
CJ
D000284:Administration, Oral; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000188:drug therapy; D001549:Benzamides / Q000037:antagonists & inhibitors / Q000737:chemistry; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007249:Inflammation / Q000188:drug therapy; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors; D008264:Macrophages / Q000378:metabolism; D008297:Male; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors*; D008956:Models, Chemical; D018448:Models, Immunological; D008958:Models, Molecular; D009000:Monocytes / Q000378:metabolism; D009025:Morpholines / Q000037:antagonists & inhibitors / Q000737:chemistry; D010024:Osteoporosis / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D011917:Rats, Inbred Lew; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism
C550450:5-tert-butyl-N-cyclopropyl-2-methoxy-3-(2-(4-(2-morpholin-4-ylethoxy)naphthalen-1-yl)-2-oxoacetylamino)benzamide; D001549:Benzamides; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D009025:Morpholines; D014409:Tumor Necrosis Factor-alpha; D048308:Mitogen-Activated Protein Kinase 14