Design and Synthesis of 4-Azaindoles as Inhibitors of p38 MAP Kinase

Inhibition of the biosynthesis of proinflammatory cytokines such as tumor necrosis factor and interleukin-1 via p38 has been an approach toward the development of a disease modifying agent for the treatment of chronic inflammation and autoimmune diseases. The development of a new core structure of p...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2003-10, Vol.46 (22), p.4702-4713
Main Authors: Trejo, Alejandra, Arzeno, Humberto, Browner, Michelle, Chanda, Sushmita, Cheng, Soan, Comer, Daniel D, Dalrymple, Stacie A, Dunten, Pete, Lafargue, JoAnn, Lovejoy, Brett, Freire-Moar, Jose, Lim, Julie, Mcintosh, Joel, Miller, Jennifer, Papp, Eva, Reuter, Deborah, Roberts, Rick, Sanpablo, Florentino, Saunders, John, Song, Kyung, Villasenor, Armando, Warren, Stephen D, Welch, Mary, Weller, Paul, Whiteley, Phyllis E, Zeng, Lu, Goldstein, David M
Format: Article
Language:English
Subjects:
Administration, Oral
Animals
Biological and medical sciences
Biological Availability
Bones, joints and connective tissue. Antiinflammatory agents
Cell Line
Crystallography, X-Ray
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
Female
Humans
Hydrogen Bonding
In Vitro Techniques
Indoles - chemical synthesis
Indoles - chemistry
Injections, Intravenous
Medical sciences
Mitogen-Activated Protein Kinase 14
Mitogen-Activated Protein Kinases - antagonists & inhibitors
Mitogen-Activated Protein Kinases - chemistry
Models, Molecular
Pharmacology. Drug treatments
Protein Binding
Protein Isoforms
Pyridines - chemical synthesis
Pyridines - chemistry
Pyridines - pharmacology
Rats
Structure-Activity Relationship
Tumor Necrosis Factor-alpha - biosynthesis
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Description
Summary:Inhibition of the biosynthesis of proinflammatory cytokines such as tumor necrosis factor and interleukin-1 via p38 has been an approach toward the development of a disease modifying agent for the treatment of chronic inflammation and autoimmune diseases. The development of a new core structure of p38 inhibitors, 3-(4-fluorophenyl)-2-(pyridin-4-yl)-1H-pyrrolo[3,2-b] pyridine, is described. X-ray crystallographic data of the lead bound to the active site of p38 was used to guide the optimization of the series. Specific focus was placed on modulating the physical properties of the core while maintaining potent inhibition of p38. These efforts identified 42c as a potent inhibitor of p38, which also possessed the required physical properties worthy of advanced studies.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm0301787