Novel potent pyrimido[4,5-c]quinoline inhibitors of protein kinase CK2: SAR and preliminary assessment of their analgesic and anti-viral properties.

Abstract

We describe the discovery of novel potent substituted pyrimido[4,5-c]quinoline ATP-competitive inhibitors of protein kinase CK2. A binding model of the inhibitors with the protein was elaborated on the basis of SAR and revealed various modes of interaction with the hinge region. Representative analog 14k (CK2 IC(50)=9 nM) showed anti-viral activity at nanomolar concentrations against HIV-1. Orally available compound 7e (CK2 IC(50)=3 nM) reduced pain in the phase II of a murine formalin model. These preliminary data confirm that properly optimized CK2 inhibitors may be used for anti-viral and pain therapy.

• Authors: Fabrice Pierre, Sean E O'Brien, Mustapha Haddach, Pauline Bourbon, Michael K Schwaebe, Eric Stefan, Levan Darjania, Ryan Stansfield, Caroline Ho, Adam Siddiqui-Jain, Nicole Streiner, William G Rice, Kenna Anderes, David M Ryckman
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 21 Issue 6 Pg. 1687-91 (Mar 15 2011) ISSN: 1464-3405 [Electronic] England
• PMID: 21316963 (Publication Type: Journal Article)
• Copyright: Copyright © 2011 Elsevier Ltd. All rights reserved.

Chemical References

• Analgesics
• Antiviral Agents
• Enzyme Inhibitors
• Quinolines
• Casein Kinase II

Topics

• Analgesics (chemistry, pharmacology)
• Antiviral Agents (chemistry, pharmacology)
• Casein Kinase II (antagonists & inhibitors)
• Enzyme Inhibitors (chemistry, pharmacology)
• Hydrogen Bonding
• Quinolines (chemistry, pharmacology)
• Structure-Activity Relationship