Biomedical
Electrochemical Synthesis of the In Human S-oxide Metabolites of Phenothiazine-Containing Antipsychotic Medications
Ridho Asra,
Aigul Erbosynovna Malmakova,
Alan M. Jones
Peer Reviewed
Abstract
Abstract
The tractable preparation of Phase I drug metabolites is a critical step to understand the first-pass behaviour of novel chemical entities (NCEs) in drug discovery. In this study, we have developed a structure–electroactivity relationship (SeAR)-informed electrochemical reaction of the parent 2-chlorophenothiazine and the antipsychotic medication, chlorpromazine. With the ability to dial-in under current controlled conditions, the formation of S-oxide and novel S,S-dioxide metabolites has been achieved for the first time on a multi-milligram scale using a direct batch electrode platform. A potential rationale for the electrochemical formation of these metabolites in situ is proposed using molecular docking to a cytochrome P450 enzyme.
Key Questions
1. What is the significance of preparing Phase I drug metabolites in drug discovery?
Preparing Phase I drug metabolites is crucial for understanding the first-pass metabolism of novel chemical entities, which influences their pharmacokinetics and potential efficacy in drug discovery.
2. How does the electrochemical synthesis method developed in this study improve metabolite production?
The study introduces a structure–electroactivity relationship (SeAR)-informed electrochemical reaction that enables controlled formation of S-oxide and novel S,S-dioxide metabolites on a multi-milligram scale, enhancing efficiency in metabolite production.
3. What role does molecular docking to cytochrome P450 enzymes play in this research?
Molecular docking to cytochrome P450 enzymes provides a rationale for the in situ electrochemical formation of metabolites, offering insights into the metabolic pathways of compounds like chlorpromazine.
4. Why is chlorpromazine used as a model compound in this study?
Chlorpromazine, an antipsychotic medication, serves as a model compound due to its well-known metabolic profile, making it suitable for evaluating the effectiveness of the electrochemical synthesis method.
5. What is the role of electrochemistry in drug metabolism studies?
Electrochemistry simulates oxidative metabolic reactions, allowing for the generation and study of drug metabolites without the need for complex biological systems.
6. How does molecular docking aid in drug design?
Molecular docking predicts the interaction between drugs and their target proteins, assisting in the optimization of drug efficacy and safety profiles during the design process.
