Improvement of Cell Permeability of Human Neuronal Nitric Oxide Synthase Inhibitors Using Potent and Selective 2-Aminopyridine-Based Scaffolds with a Fluorobenzene Linker

Abstract

Inhibition 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 = 26 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.

First Contact: 7-Phenyl-2-Aminoquinolines, Potent and Selective Neuronal Nitric Oxide Synthase Inhibitors That Target an Isoform-Specific Aspartate

“… a All assays were performed over 17 h at a concentration of 200 μM; see the Experimental Section for details. b log D (pH = 7.4) and log P values of the free-base species were predicted using ChemAxon software. c TPSA calculations and BBB permeation were predicted using the free web tool SwissADME. d Effective permeability values from the literature e Effective permeability values obtained in-house. f Experimental P e values reported previously by Do et al …”

“…Additional purification of the crude product was achieved after reverse phase flash column chromatography, eluting through a 15.5 g C18 RediSep RF Gold cartridge column with a gradient of 100% water to 100% acetonitrile to afford pure 36 as a cream-colored solid (0.011 g, 47% from 135) after azeotropic removal of water with toluene and drying in vacuo: mp > 151 °C (slowly browns) 253−254 °C. 1 (37). Compounds 39 (0.081 g, 0.265 mmol) and 116 (0.127 g, 0.32 mmol) were coupled using General Procedure 1.…”

Improved Brain Delivery of Pueraria Flavones Via Intranasal Administration Of Borneol-Modified Solid Lipid Nanoparticles

“…Caco-2 cells, which are derived from intestinal mucosa and retained the natural functions of typical absorption epithelium are an attractive candidate as a model of the nasal mucosa epithelial [32][33][34]. Here, it was chosen as an easy nasal mucosa model to study the nasal mucosa absorption which can indicate the brain delivery property of Bo-SA-SLNs and Bo-SLNs after intranasal delivery in vitro [35,36]. After intranasal delivery, SLNs should first be uptaked by the nasal mucosa cells to transport to the brain.…”

Targeting iNOS As a Valuable Strategy for the Therapy of Glioma

“…Moreover, from the reaction with the superoxide anion (O 2 − ), NO generates the potent oxidant peroxynitrite (ONOO − ) which is responsible for oxidative damage, nitration, and S‐nitrosylation of biomolecules including proteins, lipids, and DNA. Considering the pathological role of NO, many potent and selective NOS inhibitors were developed to treat different pathological states in which NO overproduction is implicated . Very recently, an almost complete review regarding the structural features and biological applications of disclosed iNOS inhibitors was published .…”