Synthesis and biological evaluation of N-mercaptoacylcysteine derivatives as leukotriene A4 hydrolase inhibitors

Bioorg Med Chem Lett. 2009 Jan 15;19(2):442-6. doi: 10.1016/j.bmcl.2008.11.042. Epub 2008 Nov 18.

Abstract

We studied synthetic modifications of N-mercaptoacylamino acid derivatives to develop a new class of leukotriene A(4) (LTA(4)) hydrolase inhibitors. S-(4-Dimethylamino)benzyl-l-cysteine derivative 2a (SA6541) showed inhibitory activity against LTA(4) hydrolase (IC(50), 270nM) and selectivity over other metallopeptidases except angiotensin-converting enzyme (ACE, IC(50), 520nM). Modification at the para-substituent of the phenyl ring of compound 2a improved LTA(4) hydrolase inhibitory activity as well as selectivity over ACE. Finally, we obtained S-(4-cyclohexyl)benzy-l-cysteine derivatives 11l and 16i as potent and selective LTA(4) hydrolase inhibitors.

MeSH terms

  • Angiotensin-Converting Enzyme Inhibitors / chemical synthesis
  • Angiotensin-Converting Enzyme Inhibitors / chemistry
  • Angiotensin-Converting Enzyme Inhibitors / pharmacology
  • Cysteine / chemistry*
  • Drug Evaluation, Preclinical
  • Epoxide Hydrolases / antagonists & inhibitors*
  • Models, Molecular
  • Quantitative Structure-Activity Relationship
  • Sulfhydryl Compounds / chemical synthesis*
  • Sulfhydryl Compounds / chemistry
  • Sulfhydryl Compounds / pharmacology*

Substances

  • Angiotensin-Converting Enzyme Inhibitors
  • Sulfhydryl Compounds
  • Epoxide Hydrolases
  • Cysteine
  • leukotriene A4 hydrolase