Nitrile in the Hole: Discovery of a Small Auxiliary Pocket in Neuronal Nitric Oxide Synthase Leading to the Development of Potent and Selective 2-Aminoquinoline Inhibitors.

Abstract

Neuronal nitric oxide synthase (nNOS) inhibition is a promising strategy to treat neurodegenerative disorders, but the development of nNOS inhibitors is often hindered by poor pharmacokinetics. We previously developed a class of membrane-permeable 2-aminoquinoline inhibitors and later rearranged the scaffold to decrease off-target binding. However, the resulting compounds had decreased permeability, low human nNOS activity, and low selectivity versus human eNOS. In this study, 5-substituted phenyl ether-linked aminoquinolines and derivatives were synthesized and assayed against purified NOS isoforms. 5-Cyano compounds are especially potent and selective rat and human nNOS inhibitors. Activity and selectivity are mediated by the binding of the cyano group to a new auxiliary pocket in nNOS. Potency was enhanced by methylation of the quinoline and by introduction of simple chiral moieties, resulting in a combination of hydrophobic and auxiliary pocket effects that yielded high (∼500-fold) n/e selectivity. Importantly, the Caco-2 assay also revealed improved membrane permeability over previous compounds.

• Authors: Maris A Cinelli, Huiying Li, Georges Chreifi, Thomas L Poulos, Richard B Silverman
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 60 Issue 9 Pg. 3958-3978 (05 11 2017) ISSN: 1520-4804 [Electronic] United States
• PMID: 28422508 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Aminoquinolines
• Enzyme Inhibitors
• Nitriles
• Nitric Oxide Synthase Type I

Topics

• Aminoquinolines (pharmacology)
• Animals
• Drug Discovery
• Enzyme Inhibitors (chemistry, pharmacology)
• Humans
• Nitric Oxide Synthase Type I (antagonists & inhibitors, chemistry)
• Nitriles (chemistry)
• Rats