First Contact: 7-Phenyl-2-Aminoquinolines, Potent and Selective Neuronal Nitric Oxide Synthase Inhibitors That Target an Isoform-Specific Aspartate

Maris A Cinelli; Cory T Reidl; Huiying Li; Georges Chreifi; Thomas L Poulos; Richard B Silverman

doi:10.1021/acs.jmedchem.9b01573

First Contact: 7-Phenyl-2-Aminoquinolines, Potent and Selective Neuronal Nitric Oxide Synthase Inhibitors That Target an Isoform-Specific Aspartate

J Med Chem. 2020 May 14;63(9):4528-4554. doi: 10.1021/acs.jmedchem.9b01573. Epub 2020 Apr 17.

Authors

Maris A Cinelli¹, Cory T Reidl¹, Huiying Li², Georges Chreifi², Thomas L Poulos³, Richard B Silverman¹

Affiliations

¹ Department of Chemistry, Department of Molecular Biosciences, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, Northwestern University, 2145 Sheridan Road, Evanston, Illinois 60208-3113, United States.
² Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, California 92697-3900, United States.
³ Department of Molecular Biology and Biochemistry, Pharmaceutical Sciences, and Chemistry, University of California, Irvine, Irvine, California 92697-3900, United States.

Abstract

Inhibition of neuronal nitric oxide synthase (nNOS), an enzyme implicated in neurodegenerative disorders, is an attractive strategy for treating or preventing these diseases. We previously developed several classes of 2-aminoquinoline-based nNOS inhibitors, but these compounds had drawbacks including off-target promiscuity, low activity against human nNOS, and only modest selectivity for nNOS over related enzymes. In this study, we synthesized new nNOS inhibitors based on 7-phenyl-2-aminoquinoline and assayed them against rat and human nNOS, human eNOS, and murine and (in some cases) human iNOS. Compounds with a meta-relationship between the aminoquinoline and a positively charged tail moiety were potent and had up to nearly 900-fold selectivity for human nNOS over human eNOS. X-ray crystallography indicates that the amino groups of some compounds occupy a water-filled pocket surrounding an nNOS-specific aspartate residue (absent in eNOS). This interaction was confirmed by mutagenesis studies, making 7-phenyl-2-aminoquinolines the first aminoquinolines to interact with this residue.

Publication types

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

MeSH terms

Aminoquinolines / chemical synthesis
Aminoquinolines / metabolism
Aminoquinolines / pharmacokinetics
Aminoquinolines / pharmacology*
Animals
Aspartic Acid / chemistry*
Blood-Brain Barrier / metabolism
Catalytic Domain
Crystallography, X-Ray
Enzyme Assays
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / metabolism
Enzyme Inhibitors / pharmacokinetics
Enzyme Inhibitors / pharmacology*
Humans
Isoenzymes / antagonists & inhibitors
Isoenzymes / chemistry
Isoenzymes / genetics
Isoenzymes / metabolism
Microsomes, Liver / metabolism
Molecular Structure
Mutagenesis, Site-Directed
Mutation
Nitric Oxide Synthase Type I / antagonists & inhibitors*
Nitric Oxide Synthase Type I / chemistry
Nitric Oxide Synthase Type I / genetics
Nitric Oxide Synthase Type I / metabolism
Permeability
Protein Binding
Rats
Structure-Activity Relationship

Substances

Aminoquinolines
Enzyme Inhibitors
Isoenzymes
Aspartic Acid
NOS1 protein, human
Nitric Oxide Synthase Type I

Abstract

Publication types

MeSH terms

Substances

Grants and funding