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Fluoroalkylation of Dextromethorphan Improves CNS Exposure and Metabolic Stability

preprint
submitted on 27.04.2021, 15:14 and posted on 28.04.2021, 09:11 by Jacob Sorrentino, Ryan Altman

Aryl-methyl ethers, while present in many bioactive compounds, are subject to rapid O-dealkylation that can generate bio-inactive or toxic metabolites. 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 fluoroalkyl analogs of dextromethorphan that display improved pharmacokinetic profiles relative to dextromethorphan and related analogs currently in clinical trials. Specifically, the fluorinated analogs minimized metabolic degradation and increased CNS exposure relative to DXM in vivo. Ultimately, these fluorinated motifs might be applicable to other aryl-methyl ether containing compounds as a strategy to improve pharmacokinetic profiles.

Funding

Fluoroalkylethers and Fluorinated Ethermimetics

National Institute of General Medical Sciences

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AVIII HD 400 NMR spectrometer to replace existing DRX 400

Office of the Director

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Avance II 500 High Performance Digital NMR Spectrometer System

National Center for Advancing Translational Sciences

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Kansas IDeA Network of Biomedical Research Excellence (K-INBRE)

National Institute of General Medical Sciences

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MRI: Upgrade of a 500 MHz Nuclear Magnetic Resonance Spectrometer

Directorate for Mathematical & Physical Sciences

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MRI: Acquisition of a Multinuclear Broadband Cryogenically Cooled Probe for NMR Spectroscopy at KU-Lawrence

Directorate for Mathematical & Physical Sciences

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MRI: Acquisition of Cryoprobe/Cryoplatform for 500 MHz NMR

Directorate for Mathematical & Physical Sciences

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History

Email Address of Submitting Author

raaltman@purdue.edu

Institution

Purdue University

Country

United States

ORCID For Submitting Author

0000-0002-8724-1098

Declaration of Conflict of Interest

The authors declare no competing financial interest.

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