Synthesis and biological evaluation of N-mercaptoacylproline and N-mercaptoacylthiazolidine-4-carboxylic acid derivatives as leukotriene A4 hydrolase inhibitors

Bioorg Med Chem Lett. 2008 Aug 15;18(16):4529-32. doi: 10.1016/j.bmcl.2008.07.043. Epub 2008 Jul 15.

Abstract

We studied the synthetic modification of structurally similar N-mercaptoacyl-L-proline and (4R)-N-mercaptoacylthiazolidine-4-carboxylic acid to obtain potent leukotriene A(4) (LTA(4)) hydrolase inhibitors. An N-mercaptoacyl group, (2S)-3-mercapto-2-methylpropionyl group, was effective for both scaffolds. Additional introduction of a large substituent such as 4-isopropylbenzylthio (3f), 4-tert-butylbenzylthio (3l) or 4-cyclohexylbenzylthio group (3m) with (S)-configuration at the C(4) position of proline yielded much more potent LTA(4) hydrolase inhibitors (IC(50); 52, 31, and 34 nM, respectively) than captopril (IC(50); 630,000 nM).

MeSH terms

  • Animals
  • Carboxylic Acids / chemical synthesis*
  • Carboxylic Acids / chemistry
  • Chemistry, Pharmaceutical / methods
  • Crystallography, X-Ray / methods
  • Drug Design
  • Epoxide Hydrolases / antagonists & inhibitors*
  • Humans
  • Inhibitory Concentration 50
  • Leukotriene A4 / metabolism
  • Models, Chemical
  • Proline / analogs & derivatives*
  • Proline / chemical synthesis*
  • Proline / chemistry
  • Proline / pharmacology
  • Structure-Activity Relationship
  • Sulfhydryl Compounds / pharmacology*
  • Thiazolidines / pharmacology*

Substances

  • Carboxylic Acids
  • Leukotriene A4
  • Sulfhydryl Compounds
  • Thiazolidines
  • Proline
  • Epoxide Hydrolases
  • leukotriene A4 hydrolase