Aryl-methyl ethers, while present in many bioactive compounds, are subject to rapid O-dealkylation that can generate bio-inactive or toxic metabolites. In this process, P450-mediated oxidation generates a formyl hemi-acetal intermediate that subsequently undergoes hydrolysis to reveal a phenol. To combat this process, the strategic use of fluorinated substituents can disfavor P450 mediated oxidation, which in turn, can reduced metabolic liabilities. As an example, the cough suppressant dextromethorphan undergoes such a P450 mediated O-dealkylation to provide the psychoactive phenolic metabolite dextrorphan. This metabolite antagonizes the NMDA receptor causing hallucinations, which encourages recreational abuse. To circumvent this undesired metabolism, we have designed, synthesized, and evaluated in vitro and in vivo new fluorinated analogs of dextromethorphan with improved pharmacokinetic and pharmacodynamic profiles. Evaluation of the pharmacodynamic profile revealed that select compounds in the series bound with nanomolar affinity to monoamine transporters that are known targets for treating depression and anxiety disorders, as well as other CNS disease states. Additionally, the CNS receptor binding profiles are more selective than other classes of drugs used to modulate these transporters. Moreover, these fluorinated analogs display improved pharmacokinetic profiles relative to dextromethorphan and related analogs currently in clinical trials. Ultimately, the substitution of the aryl-methyl ether in DXM with fluorinated mimics minimized metabolic degradation of the analogs, increased CNS exposure, and improved selectivity for monoamine transporters.

Fluorinated dextromethorphan analogs to prevent the formation of psychoactive metabolites

ACS Spring Meeting 2021

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