Abstract |
A series of N-aryl pyridinone inhibitors of p38 mitogen activated protein (MAP) kinase were designed and prepared based on the screening hit SC-25028 (1) and structural comparisons to VX-745 (5). The focus of the investigation targeted the dependence of potency and metabolic stability on the benzyloxy connectivity, the role of the C-6 position and the substitution pattern on the N-phenyl ring. Further optimization produced the highly selective and potent pyridinones 2 and 3. These inhibitors exhibited activity in both acute and chronic models of inflammation.
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Authors | Shaun R Selness, Terri L Boehm, John K Walker, Balekudru Devadas, Richard C Durley, Ravi Kurumbail, Huey Shieh, Li Xing, Michael Hepperle, Paul V Rucker, Kevin D Jerome, Alan G Benson, Laura D Marrufo, Heather M Madsen, Jeff Hitchcock, Tom J Owen, Lance Christie, Michele A Promo, Brian S Hickory, Edgardo Alvira, Win Naing, Radhika Blevis-Bal, Rajesh V Devraj, Dean Messing, John F Schindler, Jeffrey Hirsch, Matthew Saabye, Sheri Bonar, Elizabeth Webb, Gary Anderson, Joseph B Monahan |
Journal | Bioorganic & medicinal chemistry letters
(Bioorg Med Chem Lett)
Vol. 21
Issue 13
Pg. 4059-65
(Jul 01 2011)
ISSN: 1464-3405 [Electronic] England |
PMID | 21640588
(Publication Type: Journal Article)
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Copyright | Copyright © 2011 Elsevier Ltd. All rights reserved. |
Chemical References |
- Enzyme Inhibitors
- Pyridazines
- Pyridones
- Pyrimidines
- p38 Mitogen-Activated Protein Kinases
- VX-745
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Topics |
- Animals
- Disease Models, Animal
- Drug Design
- Enzyme Activation
(drug effects)
- Enzyme Inhibitors
(chemical synthesis, chemistry, pharmacology)
- Humans
- Inhibitory Concentration 50
- Male
- Microsomes, Liver
(enzymology)
- Molecular Structure
- Pyridazines
(chemistry, pharmacology)
- Pyridones
(chemical synthesis, chemistry, pharmacology)
- Pyrimidines
(chemistry, pharmacology)
- Rats
- Rats, Sprague-Dawley
- p38 Mitogen-Activated Protein Kinases
(antagonists & inhibitors)
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