Synthesis and evaluation of new omega-borono-alpha-amino acids as rat liver arginase inhibitors

Bioorg Med Chem. 2005 Apr 1;13(7):2373-9. doi: 10.1016/j.bmc.2005.01.053.

Abstract

Recent studies have demonstrated that arginase plays important roles in pathologies such as asthma or erectile dysfunctions. We have synthesized new omega-borono-alpha-amino acids that are analogues of the previously known arginase inhibitors S-(2-boronoethyl)-l-cysteine (BEC) and 2-amino-6-boronohexanoic acid (ABH) and evaluated them as inhibitors of purified rat liver arginase (RLA). In addition to the distance between the B(OH)(2) and the alpha-amino acid functions, the position of the sulfur atom in the side chain also appears as a key determinant for the interaction with the active site of RLA. Furthermore, substitution of the alkyl side chain of BEC by methyl groups and conformational restriction of ABH by incorporation of its side chain in a phenyl ring led to inactive compounds. These results suggest that subtle interactions govern the affinity of inhibitors for the active site of RLA.

MeSH terms

  • Amino Acids / chemical synthesis*
  • Amino Acids / chemistry
  • Amino Acids / pharmacology*
  • Animals
  • Arginase / antagonists & inhibitors*
  • Arginase / metabolism
  • Boron Compounds / chemistry*
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Liver / enzymology
  • Liver / metabolism
  • Male
  • Molecular Structure
  • Rats
  • Rats, Sprague-Dawley
  • Structure-Activity Relationship

Substances

  • Amino Acids
  • Boron Compounds
  • Enzyme Inhibitors
  • Arginase