Novel and orally bioavailable inducible nitric oxide synthase inhibitors: synthesis and evaluation of optically active 4,5-dialkyl-2-iminoselenazolidine derivatives

Bioorg Med Chem Lett. 2005 Mar 1;15(5):1361-6. doi: 10.1016/j.bmcl.2005.01.013.

Abstract

We have previously reported that (4R,5R)-5-ethyl-2-imino-4-methylthiazolidine (3) strongly inhibits inducible nitric oxide synthase (iNOS). In a successive search for strong and selective iNOS inhibitors, we, herein, describe the synthesis of the selenium analogue of 3 (4: ES-2133) and its related optically active compounds and examine their in vitro and in vivo inhibitory activity against iNOS. In addition, an alternative synthetic method to the selected compound 4 and its pharmacokinetic profile is also reported.

MeSH terms

  • Arginine / antagonists & inhibitors
  • Biological Availability
  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacokinetics*
  • Kinetics
  • Molecular Conformation
  • Nitric Oxide Synthase / antagonists & inhibitors*
  • Nitric Oxide Synthase Type II
  • Organoselenium Compounds / chemical synthesis*
  • Organoselenium Compounds / chemistry
  • Organoselenium Compounds / pharmacokinetics*
  • Selenium / chemistry
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Organoselenium Compounds
  • Arginine
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • Selenium