Hydrophilic, Potent, and Selective 7‑Substituted 2‑Aminoquinolines as Improved Human Neuronal Nitric Oxide Synthase Inhibitors

Neuronal nitric oxide synthase (nNOS)
is a target for development
of antineurodegenerative agents. Most nNOS inhibitors mimic l-arginine and have poor bioavailability. 2-Aminoquinolines showed
promise as bioavailable nNOS inhibitors but suffered from low human
nNOS inhibition, low selectivity versus human eNOS, and significant
binding to other CNS targets. We aimed to improve human nNOS potency
and selectivity and reduce off-target binding by (a) truncating the
original scaffold or (b) introducing a hydrophilic group to interrupt
the lipophilic, promiscuous pharmacophore and promote interaction
with human nNOS-specific His342. We synthesized both truncated and
polar 2-aminoquinoline derivatives and assayed them against recombinant
NOS enzymes. Although aniline and pyridine derivatives interact with
His342, benzonitriles conferred the best rat and human nNOS inhibition.
Both introduction of a hydrophobic substituent next to the cyano group
and aminoquinoline methylation considerably improved isoform selectivity.
Most importantly, these modifications preserved Caco-2 permeability
and reduced off-target CNS binding.