An Unexpected Deuterium-Induced Metabolic Switch in Doxophylline

Silvio Aprile; Giorgia Colombo; Marta Serafini; Rosanna Di Paola; Federica Pisati; Irene Preet Bhela; Salvatore Cuzzocrea; Giorgio Grosa; Tracey Pirali

doi:10.1021/acsmedchemlett.2c00166

An Unexpected Deuterium-Induced Metabolic Switch in Doxophylline

Silvio Aprile, Giorgia Colombo, Marta Serafini, Rosanna Di Paola, Federica Pisati, Irene Preet Bhela, Salvatore Cuzzocrea, Giorgio Grosa, Tracey Pirali

Department of Pharmaceutical Sciences

Research output: Contribution to journal › Article › peer-review

Abstract

Precision deuteration has become part of the medicinal chemist's toolbox, but its usefulness can be undermined by unpredictable metabolic switch effects. Herein we report the deuteration of doxophylline, a drug used in the treatment of asthma and COPD that undergoes extensive oxidative metabolism. Labeling of the main metabolic soft spots triggered an unexpected multidirectional metabolic switch that, while not improving the pharmacokinetic parameters, changed the metabolic scenario and, in turn, the pharmacodynamic features in two murine models of lung injury.

Original language	English
Pages (from-to)	1278-1285
Number of pages	8
Journal	ACS Medicinal Chemistry Letters
Volume	13
Issue number	8
DOIs	https://doi.org/10.1021/acsmedchemlett.2c00166
Publication status	Published - 11 Aug 2022

Keywords

Deuterium
deuterium kinetic isotope effect
doxophylline
metabolic switch

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10.1021/acsmedchemlett.2c00166

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AU - Serafini, Marta

AU - Di Paola, Rosanna

AU - Pisati, Federica

AU - Bhela, Irene Preet

AU - Cuzzocrea, Salvatore

AU - Grosa, Giorgio

AU - Pirali, Tracey

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AB - Precision deuteration has become part of the medicinal chemist's toolbox, but its usefulness can be undermined by unpredictable metabolic switch effects. Herein we report the deuteration of doxophylline, a drug used in the treatment of asthma and COPD that undergoes extensive oxidative metabolism. Labeling of the main metabolic soft spots triggered an unexpected multidirectional metabolic switch that, while not improving the pharmacokinetic parameters, changed the metabolic scenario and, in turn, the pharmacodynamic features in two murine models of lung injury.

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KW - metabolic switch

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An Unexpected Deuterium-Induced Metabolic Switch in Doxophylline

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Keywords

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