Heteroalicyclic carboxamidines as inhibitors of inducible nitric oxide synthase; the identification of (2R)-2-pyrrolidinecarboxamidine as a potent and selective haem-co-ordinating inhibitor

Bioorg Med Chem Lett. 2011 May 15;21(10):3037-40. doi: 10.1016/j.bmcl.2011.03.038. Epub 2011 Mar 21.

Abstract

Heteroalicyclic carboxamidines were synthesised and evaluated as inhibitors of nitric oxide synthases. (2R)-2-Pyrrolidinecarboxamidine, in particular, was shown to be a highly potent in vitro (IC(50)=0.12 μM) and selective iNOS inhibitor (>100-fold vs both eNOS and nNOS), with probable binding to the key anchoring glutamate residue and co-ordination to the haem iron.

MeSH terms

  • Amidines / chemical synthesis*
  • Amidines / chemistry
  • Amidines / pharmacology*
  • Enzyme Activation / drug effects*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Heme / antagonists & inhibitors*
  • Heterocyclic Compounds / chemical synthesis*
  • Heterocyclic Compounds / chemistry
  • Heterocyclic Compounds / pharmacology
  • Humans
  • Inhibitory Concentration 50
  • Models, Molecular
  • Molecular Structure
  • Nitric Oxide Synthase Type II / antagonists & inhibitors*
  • Proline / analogs & derivatives*
  • Proline / chemical synthesis
  • Proline / chemistry
  • Proline / pharmacology

Substances

  • Amidines
  • Enzyme Inhibitors
  • Heterocyclic Compounds
  • Heme
  • Proline
  • Nitric Oxide Synthase Type II
  • prolinamide