Conformationally restricted dipeptide amides as potent and selective neuronal nitric oxide synthase inhibitors

J Med Chem. 2006 Oct 19;49(21):6254-63. doi: 10.1021/jm0604124.

Abstract

Four new conformationally restricted analogues of a potent and selective neuronal nitric oxide synthase inhibitor, l-nitroargininyl-l-2,4-diaminobutyramide (1), have been synthesized. N(alpha)-Methyl and N(alpha)-benzyl derivatives (3 and 4, respectively) of 4-N-(l-Arg(NO(2))-trans-4-amino-l-prolineamide (2) are also selective inhibitors, but the potency and selectivity of 3 are weak. Analogue 4 has only one-third the potency and one-half to one-third the selectivity of 2 against iNOS (inducible nitric oxide synthase) and eNOS (endothelial nitric oxide synthase), respectively. 3-N-(l-Arg(NO)(2))-trans-3-amino-l-prolineamide (6) is as potent an inhibitor of nNOS (neuronal nitric oxide synthase) as 2; selectivity for nNOS over iNOS is half of that for 2, but the selectivity for nNOS over eNOS is almost double that for 2. The corresponding cis-isomer (5) is a weak inhibitor of nNOS. These results are supported by computer modeling.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amides / chemical synthesis*
  • Amides / chemistry
  • Dipeptides / chemical synthesis*
  • Dipeptides / chemistry
  • Models, Molecular
  • Molecular Conformation
  • Nitric Oxide Synthase Type I / antagonists & inhibitors*
  • Nitric Oxide Synthase Type I / chemistry
  • Nitric Oxide Synthase Type II / antagonists & inhibitors
  • Nitric Oxide Synthase Type II / chemistry
  • Nitric Oxide Synthase Type III / antagonists & inhibitors
  • Nitric Oxide Synthase Type III / chemistry
  • Proline / analogs & derivatives
  • Proline / chemical synthesis
  • Proline / chemistry
  • Structure-Activity Relationship

Substances

  • Amides
  • Dipeptides
  • Proline
  • Nitric Oxide Synthase Type I
  • Nitric Oxide Synthase Type II
  • Nitric Oxide Synthase Type III