Pyrazoles and pyrazolines as neural and inducible nitric oxide synthase (nNOS and iNOS) potential inhibitors (III)

Eur J Med Chem. 2008 Nov;43(11):2579-91. doi: 10.1016/j.ejmech.2008.01.014. Epub 2008 Jan 26.

Abstract

We have previously described a series of 4,5-dihydro-1H-pyrazole as moderately potent nNOS inhibitors. As a follow up of these studies, we report here the preparation and the preliminary evaluation of a series of 1-alkyl-3-benzoyl-4,5-dihydro-1H-pyrazole and 1-alkyl-3-benzoyl-1H-pyrazole as potential inhibitors of both neuronal and inducible nitric oxide synthases (nNOS and iNOS). None of the reported compounds exhibited significant iNOS or nNOS inhibition, although the 1-benzyl-3-(2-amino-5-chlorobenzoyl)-1H-pyrazole-5-carboxylic acid ethyl ester derivative (10l), which shows an inhibition of 50% versus iNOS at a 1mM final concentration and no activity against nNOS, is potentially amenable of further optimization. The reasons for the inactivity of the reported series are discussed on the basis of docking studies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkylation
  • Animals
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Male
  • Models, Molecular
  • Molecular Structure
  • Nitric Oxide Synthase Type I / antagonists & inhibitors*
  • Nitric Oxide Synthase Type I / metabolism
  • Nitric Oxide Synthase Type II / antagonists & inhibitors*
  • Nitric Oxide Synthase Type II / metabolism
  • Protein Binding
  • Pyrazoles / chemical synthesis*
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology*
  • Rats
  • Rats, Wistar
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Pyrazoles
  • pyrazole
  • Nitric Oxide Synthase Type I
  • Nitric Oxide Synthase Type II