PDF(Pubmed)
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.
摘要：
I期药物代谢物的易于处理的制备是了解新型化学实体（NCE）在药物发现中的首过行为的关键步骤。在这项研究中,我们已经开发了母体2-氯噻嗪和抗精神病药物的结构-电活性关系（SeAR）-信息电化学反应，氯丙嗪.能够在当前受控条件下拨入，S-氧化物和新型S的形成，使用直接分批电极平台首次在多毫克规模上实现了S-二氧化代谢物。使用分子对接到细胞色素P450酶，提出了原位电化学形成这些代谢物的潜在原理。
