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

Dipartimento di Scienze del Farmaco

Risultato della ricerca: Contributo su rivista › Articolo in rivista › 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.

Lingua originale	Inglese
pagine (da-a)	1278-1285
Numero di pagine	8
Rivista	ACS Medicinal Chemistry Letters
Volume	13
Numero di pubblicazione	8
DOI	https://doi.org/10.1021/acsmedchemlett.2c00166
Stato di pubblicazione	Pubblicato - 11 ago 2022

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10.1021/acsmedchemlett.2c00166

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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.",

keywords = "Deuterium, deuterium kinetic isotope effect, doxophylline, metabolic switch",

author = "Silvio Aprile and Giorgia Colombo and Marta Serafini and {Di Paola}, Rosanna and Federica Pisati and Bhela, {Irene Preet} and Salvatore Cuzzocrea and Giorgio Grosa and Tracey Pirali",

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AU - Aprile, Silvio

AU - Colombo, Giorgia

AU - Serafini, Marta

AU - Di Paola, Rosanna

AU - Pisati, Federica

AU - Bhela, Irene Preet

AU - Cuzzocrea, Salvatore

AU - Grosa, Giorgio

AU - Pirali, Tracey

PY - 2022/8/11

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N2 - 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.

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.

KW - Deuterium

KW - deuterium kinetic isotope effect

KW - doxophylline

KW - metabolic switch

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JO - ACS Medicinal Chemistry Letters

JF - ACS Medicinal Chemistry Letters

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ER -

An Unexpected Deuterium-Induced Metabolic Switch in Doxophylline

Abstract

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