Potent and Selective Human Neuronal Nitric Oxide Synthase Inhibition by Optimization of the 2‑Aminopyridine-Based Scaffold with a Pyridine Linker

Neuronal
nitric oxide
synthase (nNOS) is an important therapeutic
target for the treatment of various neurodegenerative disorders. A
major challenge in the design of nNOS inhibitors focuses on potency
in humans and selectivity over other NOS isoforms. Here we report
potent and selective human nNOS inhibitors based on the 2-aminopyridine
scaffold with a central pyridine linker. Compound 14j, the most promising inhibitor in this study, exhibits excellent
potency for rat nNOS (Ki = 16 nM) with
828-fold n/e and 118-fold n/i selectivity with a Ki value of 13 nM against human nNOS with 1761-fold human
n/e selectivity. Compound 14j also displayed good metabolic
stability in human liver microsomes, low plasma protein binding, and
minimal binding to cytochromes P450 (CYPs), although it had little
to no Caco-2 permeability.