Alix, F., et al. Dihydroquinoline Carbamate DQS1-02 as a Prodrug of a Potent Acetylcholinesterase Inhibitor for Alzheimer’s Disease Therapy: Multigram-Scale Synthesis, Mechanism Investigations, in Vitro Safety Pharmacology, and Preliminary in Vivo Toxicology Profile. ACS OMEGA. 3(12), 18387−18397. 27/12/2018.

We previously characterized a set of potent pseudo-irreversible inhibitors of acetylcholinesterase (AChE) based on a redox prodrug strategy. Among the various synthesized prodrugs, compound 1, namely DQS1-02, displayed favorable physicochemical properties and was chosen to achieve the necessary prerequisite investigations prior to preclinical evaluation. Herein, we first report a practical multigram-scale nine-step synthesis of prodrug 1 with a good overall yield (18%) as well as a full investigation on the inhibition mechanism of AChE by the parent drug 2 by means of UV−vis spectroscopy, NMR, and tandem mass spectrometry. In the second part, we describe the ADME properties of DQS1-02, the safety pharmacology of both compounds 1 and 2, and the preliminary results of an in vivo toxicology study in rats. Last but not the least, we also demonstrated that AChE inhibitor 2 was highly selective for AChE, whereas the corresponding prodrug 1 proved to be remarkably safe, making it a valuable preclinical candidate.