Reversible oxidation/reduction steps in the metabolic degradation of the glycerol side chain of the S1P₁ modulator ponesimod

Abstract

1. Ponesimod is a selective modulator of the sphingosine 1-phosphate receptor 1 (S1P₁) approved for the treatment of active relapsing forms of multiple sclerosis. The chemical structure of ponesimod contains a glycerol side chain which is the major target of drug metabolism in humans.

2.  The two major metabolic pathways give the acids M12 (-OCH₂CH(OH)COOH) and M13 (-OCH₂COOH). While the former results from oxidation of the terminal alcohol, the mechanism yielding the chain-shortened acid M13 is less obvious. A detailed mechanistic study with human liver microsomes and hepatocytes using ponesimod, M12 and some of the suspected intermediates revealed an unexpectedly complex pattern of enzyme-mediated and chemical reactions.

3. Metabolic pathways for both acids were not independent and several of the transformations were reversible, depending on reaction conditions. Formation of M13 occurred either via initial oxidation of the secondary alcohol, or as a downstream process starting from M12.

4. The phenol metabolite M32 was produced as part of several pathways. Control experiments at various pH values and in the absence of metabolising enzymes support the conclusion that its formation resulted from chemical degradation rather than from metabolic processes.

Keywords:

• Ponesimod
• S1P₁ receptor modulator
• metabolism
• glycerol side chain
• oxidation
• reduction
• reversibility

Acknowledgments

The authors would like to thank Florian Willecke, Tommaso Miraval, Markus Schäuble, Sibylle Fläschel, Ali Selimi, Thomas Pfeifer, Jürgen Seifert, and Alexandre Flock for their dedication and experimental support.

Disclosure statement statement

The authors declare no conflict of interest. All experiments described in this report have been conducted in the research facilities of Actelion Pharmaceuticals Ltd. In 2017, Actelion Pharmaceuticals Ltd was acquired by Johnson & Johnson, and its drug discovery and early development activities subsequently transferred into a newly created company, Idorsia Pharmaceuticals Ltd. All authors were employees of Actelion or Idorsia Pharmaceuticals at the time of experimental conduct or manuscript writing.

Data availability

The authors confirm that the data supporting the findings of this study are available within the article.

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Funding

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