Design and synthesis of potent pyridazine inhibitors of p38 MAP kinase.
Novel potent trisubstituted pyridazine inhibitors of p38 MAP (mitogen activated protein) kinase are described that have activity in both cell-based assays of cytokine release and animal models of rheumatoid arthritis. They demonstrated potent inhibition of LPS-induced TNF-alpha production in mice and exhibited good efficacy in the rat collagen induced arthritis model.
Tamayo
Nuria
N
Chemistry Research and Discovery, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA. ntamayo@amgen.com
Liao
Lillian
L
Goldberg
Martin
M
Powers
David
D
Tudor
Yan-Yan
YY
Yu
Violeta
V
Wong
Lu Min
LM
Henkle
Bradley
B
Middleton
Scot
S
Syed
Rashid
R
Harvey
Timothy
T
Jang
Graham
G
Hungate
Randall
R
Dominguez
Celia
C
D001665:Binding Sites; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D007202:Indicators and Reagents; D007700:Kinetics; D008862:Microsomes, Liver / Q000201:enzymology; D008958:Models, Molecular; D015394:Molecular Structure; D011487:Protein Conformation; D011724:Pyridazines / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry
D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D011724:Pyridazines; D048051:p38 Mitogen-Activated Protein Kinases