Indole-based heterocyclic inhibitors of p38alpha MAP kinase: designing a conformationally restricted analogue

• Published in: Bioorganic & medicinal chemistry letters Vol. 13; no. 18; p. 3087
• Main Authors: Mavunkel, Babu J, Chakravarty, Sarvajit, Perumattam, John J, Luedtke, Gregory R, Liang, Xi, Lim, Don, Xu, Yong-jin, Laney, Maureen, Liu, David Y, Schreiner, George F, Lewicki, John A, Dugar, Sundeep
• Format: Journal Article
• Language: English
• Published: England 15.09.2003
• Subjects: Animals; Anti-Inflammatory Agents - chemical synthesis; Anti-Inflammatory Agents - pharmacology; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - pharmacology; Heterocyclic Compounds - chemical synthesis; Heterocyclic Compounds - pharmacology; Humans; Indoles - chemical synthesis; Indoles - pharmacology; Inhibitory Concentration 50; Mitogen-Activated Protein Kinases - antagonists & inhibitors; p38 Mitogen-Activated Protein Kinases; Structure-Activity Relationship
• ISSN: 0960-894X

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.