Nomethiazoles: PK/PD Study of a Novel Class of Alzheimer’s Disease Therapeutics

Abstract

Since Alzheimer’s disease (AD) is a complex disease, multi-target drugs appear to be more promising in AD therapy than those targeting just one possible underlying mechanism of the disease. Therefore, a new class of hybrid molecules (Nomethiazoles) was introduced based on the role of nitric oxide in memory and neuroprotection in addition to the anti-inflammatory and neuroprotective properties of clomethiazole (CMZ). Nomethiazoles were developed through coupling of a nitrate group with the methylthiazole pharmacophore of the neuroprotectant CMZ. GT-1061, a prototype of nomethiazoles, was proved to be active in different animal models of cognition and neuroprotection, which paved the way to enter clinical trials. The major goal of this study was to evaluate the procognitive properties of two types of recently designed nomethiazoles, diaryl and triazole compounds, in step-through passive avoidance assay, a model for cognition deficit. In mice, all the novel nomethiazoles were active in reversing the cognition deficit induced by scopolamine and L-NAME (NOS inhibitor). The diaryl compounds maintained their potency longer than the triazoles. Based on the hypothesized involvement of GABA potentiation by nomethiazole, sedation was measured by accelerated rotarod performance task and compared with CMZ and GT-1061. The novel nomethiazoles were less sedative than CMZ at equimolar doses. LC-MS/MS was used to evaluate the blood brain barrier permeability of nomethiazoles. Consequently, diaryl compounds were shown to produce a higher brain plasma concentration ratio than triazole compounds. The OH metabolites formed from nomethiazoles were also detected in mice brain samples and were correlated with the sedative activity of these hybrid molecules. The study not only proved the brain bioavailability of novel nomethiazoles, but also demonstrated their procognitive action accompanied with less sedative activity when compared with CMZ and GT-1061