Synthesis of glutamic acid analogs as potent inhibitors of leukotriene A4 hydrolase

Bioorg Med Chem. 2008 May 1;16(9):4963-83. doi: 10.1016/j.bmc.2008.03.042. Epub 2008 Mar 20.

Abstract

Leukotriene B(4) (LTB(4)) is a potent pro-inflammatory mediator that has been implicated in the pathogenesis of multiple diseases, including psoriasis, inflammatory bowel disease, multiple sclerosis and asthma. As a method to decrease the level of LTB(4) and possibly identify novel treatments, inhibitors of the LTB(4) biosynthetic enzyme, leukotriene A(4) hydrolase (LTA(4)-h), have been explored. Here we describe the discovery of a potent inhibitor of LTA(4)-h, arylamide of glutamic acid 4f, starting from the corresponding glycinamide 2. Analogs of 4f are then described, focusing on compounds that are both active and stable in whole blood. This effort culminated in the identification of amino alcohol 12a and amino ester 6b which meet these criteria.

MeSH terms

  • Crystallography, X-Ray
  • Drug Evaluation, Preclinical
  • Epoxide Hydrolases / antagonists & inhibitors*
  • Glutamic Acid / analogs & derivatives
  • Glutamic Acid / chemical synthesis*
  • Glutamic Acid / pharmacology*
  • Humans
  • Hydrogen Bonding
  • Inhibitory Concentration 50
  • Models, Molecular
  • Molecular Structure
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Glutamic Acid
  • Epoxide Hydrolases
  • leukotriene A4 hydrolase