Indole-based heterocyclic inhibitors of p38alpha MAP kinase: designing a conformationally restricted analogue.
p38alpha Mitogen Activated Protein Kinase (MAP kinase) is an intracellular soluble serine threonine kinase. p38alpha kinase is activated in response to cellular stresses, growth factors and cytokines such as interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-alpha). The central role of p38alpha activation in settings of both chronic and acute inflammation has led efforts to find inhibitors of this enzyme as possible therapies for diseases such as rheumatoid arthritis, where p38alpha activation is thought to play a causal role. Herein, we report structure-activity relationship studies on a series of indole-based heterocyclic inhibitors that led to the design and identification of a new class of p38alpha inhibitors.
Mavunkel
Babu J
BJ
Scios Inc., 820 West Maude Avenue, Sunnyvale, CA 94086, USA.
Chakravarty
Sarvajit
S
Perumattam
John J
JJ
Luedtke
Gregory R
GR
Liang
Xi
X
Lim
Don
D
Xu
Yong-jin
YJ
Laney
Maureen
M
Liu
David Y
DY
Schreiner
George F
GF
Lewicki
John A
JA
Dugar
Sundeep
S
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D048051:p38 Mitogen-Activated Protein Kinases
D000893:Anti-Inflammatory Agents; D004791:Enzyme Inhibitors; D006571:Heterocyclic Compounds; D007211:Indoles; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases