Time-dependence and preliminary SAR studies in inhibition of nitric oxide synthase isoforms by homologues of thiocitrulline

Bioorg Med Chem Lett. 2003 Nov 3;13(21):3679-80. doi: 10.1016/j.bmcl.2003.08.018.

Abstract

Treatment of N(alpha)-Cbz-N(epsilon)-(2-hydroxyethylaminothiocarbonyl)-L-lysine N-(2-hydroxyethyl)amide with boiling hydrochloric acid gave N(epsilon)-(4,5-dihydrothiazol-2-yl)-L-lysine. This was a weak and non-isoform selective inhibitor of NOS, whereas N(epsilon)-aminothiocarbonyl-L-lysine and its methyl ester were potent, with IC(50)=13 and 18 microM, respectively, against human iNOS and IC(50)=3 and 8 microM, respectively, against rat nNOS. Time dependence was observed for inhibition of nNOS by the ester.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Citrulline / analogs & derivatives*
  • Citrulline / pharmacology*
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Indicators and Reagents
  • Isoenzymes / antagonists & inhibitors
  • Kinetics
  • Magnetic Resonance Spectroscopy
  • Nitric Oxide Synthase / antagonists & inhibitors*
  • Nitric Oxide Synthase Type I
  • Nitric Oxide Synthase Type II
  • Rats
  • Recombinant Proteins / chemistry
  • Structure-Activity Relationship
  • Substrate Specificity
  • Thiourea / analogs & derivatives*
  • Thiourea / pharmacology*
  • omega-N-Methylarginine / pharmacology

Substances

  • Enzyme Inhibitors
  • Indicators and Reagents
  • Isoenzymes
  • Recombinant Proteins
  • thiocitrulline
  • omega-N-Methylarginine
  • Citrulline
  • NOS1 protein, human
  • NOS2 protein, human
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type I
  • Nitric Oxide Synthase Type II
  • Nos1 protein, rat
  • Nos2 protein, rat
  • Thiourea