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

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.