Phenyl Ether- and Aniline-Containing 2-Aminoquinolines as Potent and Selective Inhibitors of Neuronal Nitric Oxide Synthase

J Med Chem. 2015 Nov 12;58(21):8694-712. doi: 10.1021/acs.jmedchem.5b01330. Epub 2015 Oct 27.

Abstract

Excess nitric oxide (NO) produced by neuronal nitric oxide synthase (nNOS) is implicated in neurodegenerative disorders. As a result, inhibition of nNOS and reduction of NO levels is desirable therapeutically, but many nNOS inhibitors are poorly bioavailable. Promising members of our previously reported 2-aminoquinoline class of nNOS inhibitors, although orally bioavailable and brain-penetrant, suffer from unfavorable off-target binding to other CNS receptors, and they resemble known promiscuous binders. Rearranged phenyl ether- and aniline-linked 2-aminoquinoline derivatives were therefore designed to (a) disrupt the promiscuous binding pharmacophore and diminish off-target interactions and (b) preserve potency, isoform selectivity, and cell permeability. A series of these compounds was synthesized and tested against purified nNOS, endothelial NOS (eNOS), and inducible NOS (iNOS) enzymes. One compound, 20, displayed high potency, selectivity, and good human nNOS inhibition, and retained some permeability in a Caco-2 assay. Most promisingly, CNS receptor counterscreening revealed that this rearranged scaffold significantly reduces off-target binding.

MeSH terms

  • Aminoquinolines / chemistry*
  • Aminoquinolines / pharmacokinetics
  • Aminoquinolines / pharmacology*
  • Caco-2 Cells
  • Crystallography, X-Ray
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Models, Molecular
  • Nitric Oxide Synthase / antagonists & inhibitors*
  • Nitric Oxide Synthase / metabolism
  • 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
  • Nitric Oxide Synthase Type III / antagonists & inhibitors
  • Nitric Oxide Synthase Type III / metabolism
  • Phenyl Ethers / chemistry*
  • Phenyl Ethers / pharmacokinetics
  • Phenyl Ethers / pharmacology*
  • Structure-Activity Relationship

Substances

  • Aminoquinolines
  • Enzyme Inhibitors
  • Phenyl Ethers
  • phenyl ether
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type I
  • Nitric Oxide Synthase Type II
  • Nitric Oxide Synthase Type III

Associated data

  • PDB/5AD4
  • PDB/5AD5
  • PDB/5AD6
  • PDB/5AD8
  • PDB/5AD9
  • PDB/5ADA
  • PDB/5ADB
  • PDB/5ADC
  • PDB/5ADD
  • PDB/5ADE
  • PDB/5ADF
  • PDB/5ADG
  • PDB/5ADI
  • PDB/5ADJ
  • PDB/5ADK
  • PDB/5ADL
  • PDB/5ADN
  • PDB/5FJ2
  • PDB/5FJ3