jm7b01356_si_001.pdf (1.03 MB)
Improvement of Cell Permeability of Human Neuronal Nitric Oxide Synthase Inhibitors Using Potent and Selective 2‑Aminopyridine-Based Scaffolds with a Fluorobenzene Linker
journal contribution
posted on 2017-11-01, 18:48 authored by Ha T. Do, Heng-Yen Wang, Huiying Li, Georges Chreifi, Thomas L. Poulos, Richard B. SilvermanInhibition of neuronal nitric oxide
synthase (nNOS) is a promising
therapeutic approach to treat neurodegenerative diseases. Recently,
we have achieved considerable progress in improving the potency and
isoform selectivity of human nNOS inhibitors bearing a 2-aminopyridine
scaffold. However, these inhibitors still suffered from too low cell
membrane permeability to enter into CNS drug development. We report
herein our studies to improve permeability of nNOS inhibitors as measured
by both PAMPA–BBB and Caco-2 assays. The most permeable compound
(12) in this study still preserves excellent potency
with human nNOS (Ki = 30 nM) and very
high selectivity over other NOS isoforms, especially human eNOS (hnNOS/heNOS
= 2799, the highest hnNOS/heNOS ratio we have obtained to date). X-ray
crystallographic analysis reveals that 12 adopts a similar
binding mode in both rat and human nNOS, in which the 2-aminopyridine
and the fluorobenzene linker form crucial hydrogen bonds with glutamate
and tyrosine residues, respectively.