Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle, WA 98195, United States.
Certara UK Limited, Simcyp Division, Level 2 Acero, 1 Concourse Way, Sheffield S1 2BJ, United Kingdom.
Bioorg Med Chem Lett. 2022 Nov 15;76:129009. doi: 10.1016/j.bmcl.2022.129009. Epub 2022 Sep 27.
Strategically replacing hydrogen with deuterium at sites of metabolism in small molecule drugs can significantly alter clearance and potentially enhance clinical safety. Bupropion is an antidepressant and smoking cessation medication with the potential to cause seizures. We hypothesized that incorporating deuterium at specific sites in bupropion may greatly reduce epimerization, potentially slow metabolism, and reduce the formation of toxic metabolites, namely hydroxybupropion which has been associated with bupropion's toxicity. Four deuterated analogues were synthesized incorporating deuterium at sites of metabolism and epimerization with the aim of altering the metabolic profile of bupropion. Spectroscopic binding and metabolism studies with bupropion and R-or S-d4 and R-or S-d10 analogs were performed with recombinant CYP2B6, human liver microsomes, and human hepatocytes. Results demonstrate that deuterated bupropion analogues exhibited 20-25% decrease in racemization and displayed a significant decrease in the formation of CYP2B6-mediated R,R - or S,S-hydroxybupropion with recombinant protein and human liver microsomes. In primary human hepatocytes, metabolism of deuterated analogs to R,R - and S,S-hydroxybupropion and threo- and erythro-hydrobupropion was significantly less than R/S-d0 bupropion. Selective deuterium substitution at metabolic soft spots in bupropion has the potential to provide a drug with a simplified pharmacokinetic profile, reduced toxicity and improved tolerability in patients.
在小分子药物的代谢部位，通过将氢战略性地替换为氘，可以显著改变清除率，并有可能提高临床安全性。安非他酮是一种抗抑郁药和戒烟药物，有引起癫痫的潜力。我们假设在安非他酮的特定部位掺入氘可能会大大减少差向异构化，潜在地减缓代谢，并减少有毒代谢物的形成，即羟安非他酮，它与安非他酮的毒性有关。我们合成了四个氘代类似物，在代谢和差向异构化部位掺入氘，旨在改变安非他酮的代谢特征。用重组 CYP2B6、人肝微粒体和人肝细胞进行了安非他酮和 R 或 S-d4 和 R 或 S-d10 类似物的光谱结合和代谢研究。结果表明，氘代安非他酮类似物的外消旋化减少了 20-25%，并显示出与重组蛋白和人肝微粒体中 CYP2B6 介导的 R,R-或 S,S-羟安非他酮形成显著减少。在原代人肝细胞中，氘代类似物代谢为 R,R-和 S,S-羟安非他酮以及 threo-和 erythro-hydrobupropion 的代谢明显少于 R/S-d0 安非他酮。在安非他酮的代谢弱点处选择性地进行氘取代，有可能提供一种药物，其药代动力学特征简化，毒性降低，患者耐受性提高。
