Aminopurine based JNK inhibitors for the prevention of ischemia reperfusion injury

Bioorg Med Chem Lett. 2012 Feb 1;22(3):1427-32. doi: 10.1016/j.bmcl.2011.12.028. Epub 2011 Dec 11.

Abstract

In this Letter we describe the optimization of an aminopurine lead (1) with modest potency and poor overall kinase selectivity which led to the identification of a series of potent, selective JNK inhibitors. Improvement in kinase selectivity was enabled by introduction of an aliphatic side chain at the C-2 position. CC-359 (2) was selected as a potential clinical candidate for diseases manifested by ischemia reperfusion injury.

MeSH terms

  • 2-Aminopurine / chemistry*
  • 2-Aminopurine / pharmacology*
  • Animals
  • Catalytic Domain
  • Dogs
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Haplorhini
  • Inhibitory Concentration 50
  • JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors*
  • Models, Molecular
  • Molecular Structure
  • Purines / chemistry*
  • Purines / pharmacology
  • Rats
  • Reperfusion Injury / drug therapy
  • Reperfusion Injury / enzymology*
  • Structure-Activity Relationship

Substances

  • CC-359
  • Enzyme Inhibitors
  • Purines
  • 2-Aminopurine
  • JNK Mitogen-Activated Protein Kinases