HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Design, synthesis and activity of a potent, selective series of N-aryl pyridinone inhibitors of p38 kinase.

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.
AuthorsShaun 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
JournalBioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 21 Issue 13 Pg. 4059-65 (Jul 01 2011) ISSN: 1464-3405 [Electronic] England
PMID21640588 (Publication Type: Journal Article)
CopyrightCopyright © 2011 Elsevier Ltd. All rights reserved.
Chemical References
  • Enzyme Inhibitors
  • Pyridazines
  • Pyridones
  • Pyrimidines
  • p38 Mitogen-Activated Protein Kinases
  • VX-745
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)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: