Structure-activity relationships of potent, selective inhibitors of neuronal nitric oxide synthase based on the 6-phenyl-2-aminopyridine structure

J Med Chem. 2004 Mar 11;47(6):1575-86. doi: 10.1021/jm030519g.

Abstract

The synthesis and structure-activity relationships of a series of 6-phenyl-2-aminopyridines that potently and selectively inhibit the neuronal isoform of nitric oxide synthase (nNOS) are described. Compound 14bi from this series exhibits potent in vivo activity in harmaline-induced cGMP formation in rat cerebellum, a functional model of nNOS inhibition, and in the PCP-induced hypermotility model in the rat. These results suggest that 14bi may be a useful reagent for evaluating potential therapeutic applications of nNOS inhibitors in the central nervous system.

MeSH terms

  • Aminopyridines / chemical synthesis*
  • Aminopyridines / chemistry
  • Aminopyridines / pharmacology
  • Animals
  • Cerebellum / drug effects
  • Cerebellum / metabolism
  • Cyclic GMP / biosynthesis
  • Male
  • Motor Activity / drug effects
  • Nitric Oxide Synthase / antagonists & inhibitors*
  • Nitric Oxide Synthase / chemistry
  • Nitric Oxide Synthase Type I
  • Rats
  • Rats, Sprague-Dawley
  • Structure-Activity Relationship
  • Tetrahydronaphthalenes / chemical synthesis*
  • Tetrahydronaphthalenes / chemistry
  • Tetrahydronaphthalenes / pharmacology

Substances

  • 6-(4-(N,N-dimethylaminoethoxy)-5,6,7,8-tetrahydronaphthalen-1-yl)pyridin-2-ylamine
  • Aminopyridines
  • Tetrahydronaphthalenes
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type I
  • Nos1 protein, rat
  • Cyclic GMP