New aromatic substituted pyrazoles as selective inhibitors of human adipocyte fatty acid-binding protein

Bioorg Med Chem Lett. 2011 May 15;21(10):2949-52. doi: 10.1016/j.bmcl.2011.03.063. Epub 2011 Mar 22.

Abstract

a-FABP is indespensible in inflammation and may serve as a new potential drug target for inflammation related diseases. We have successfully designed and synthesized a series of aromatic substituted pyrazoles as new human a-FABP inhibitors. The compounds strongly bound to the hydrophobic binding pocket of a-FABP, while showed significantly lower binding affinities to the closely related homologue protein h-FABP. The most potent and selective compound 5 g bound to a-FABP with an apparent K(i) value below 1.0 nM, while did not inhibit h-FABP at 50 μM and thus represents one of the most potent and selective a-FABP inhibitors to date. The strong binding capacity of these inhibitors was further validated by their effective blockade of inflammatory responses as determined by the production of pro-inflammatory cytokines upon LPS stimulation. Compound 5 g may serve as a lead compound for developing new effective therapeutic agent for prevention and treatment of atherosclerosis, type 2 diabetes and other inflammatory and metabolic related diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / drug effects*
  • Anti-Inflammatory Agents / chemical synthesis*
  • Anti-Inflammatory Agents / chemistry
  • Anti-Inflammatory Agents / pharmacology*
  • Drug Design
  • Fatty Acid-Binding Proteins / antagonists & inhibitors*
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Protein Binding / drug effects
  • Pyrazoles / chemical synthesis*
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology*

Substances

  • Anti-Inflammatory Agents
  • Fatty Acid-Binding Proteins
  • Pyrazoles