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Design, synthesis and activity of a potent, selective series of N-aryl pyridinone inhibitors of p38 kinase.
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2011 Jul 01; Vol. 21 (13), pp. 4059-65. Date of Electronic Publication: 2011 May 13. - Publication Year :
- 2011
-
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.<br /> (Copyright © 2011 Elsevier Ltd. All rights reserved.)
- Subjects :
- Animals
Disease Models, Animal
Enzyme Activation drug effects
Enzyme Inhibitors chemistry
Humans
Inhibitory Concentration 50
Male
Microsomes, Liver enzymology
Molecular Structure
Pyridazines chemistry
Pyridazines pharmacology
Pyridones chemistry
Pyrimidines chemistry
Pyrimidines pharmacology
Rats
Rats, Sprague-Dawley
Drug Design
Enzyme Inhibitors chemical synthesis
Enzyme Inhibitors pharmacology
Pyridones chemical synthesis
Pyridones pharmacology
p38 Mitogen-Activated Protein Kinases antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3405
- Volume :
- 21
- Issue :
- 13
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 21640588
- Full Text :
- https://doi.org/10.1016/j.bmcl.2011.04.120