A Novel Prodrug of a nNOS Inhibitor with Improved Pharmacokinetic Potential

Under different pathological conditions, aberrant induction of neuronal nitric oxide synthase (nNOS) generates overproduction of NO that can cause irreversible cell damage. The aim of this study was to develop an amidoxime prodrug of a potent nNOS inhibitor, the benzhydryl acetamidine. We synthesized the benzhydryl acetamidoxime, which was evaluated in vitro to ascertain the potential NOS inhibitory activity, as well as conducting bioconversion into the parent acetamidine. The prodrug was also profiled for in vitro physicochemical properties, by determining the lipophilicity, passive permeation through the human gastrointestinal tract and across the blood‐brain barrier by PAMPA, and chemical, enzymatic, and plasma stability. The obtained data demonstrate that the amidoxime prodrug shows an improved pharmacokinetic profile with respect to the acetamidine nNOS inhibitor, thus suggesting that it could be a promising lead compound to treat all those pathological conditions in which nNOS activity is dysregulated.
Re‐regulating nNOS: Amidoxime 2 has been developed as prodrug of a potent nNOS inhibitor, acetamidine 1. The prodrug was found to be completely converted into the acetamidine after incubation with mARC enzymes. It was profiled for its in vitro physicochemical properties, and found to have improved drug‐like properties compared to the parent amidine and promising PAMPA‐BBB penetration.