Department of Pharmaceutical Sciences , Università del Piemonte Orientale , Largo Donegani 2 , 28100 Novara , Italy.
J Med Chem. 2019 Jun 13;62(11):5276-5297. doi: 10.1021/acs.jmedchem.8b01808. Epub 2019 Jan 25.
The use of deuteration in medicinal chemistry has exploded in the past years, and the FDA has recently approved the first deuterium-labeled drug. Precision deuteration goes beyond the pure and simple amelioration of the pharmacokinetic parameters of a drug and might provide an opportunity when facing problems in terms of metabolism-mediated toxicity, drug interactions, and low bioactivation. The use of deuterium is even broader, offering the opportunity to lower the degree of epimerization, reduce the dose of coadministered boosters, and discover compounds where deuterium is the basis for the mechanism of action. Nevertheless, designing, synthesizing, and developing a successful deuterated drug is far from straightforward, and the translation from concept to practice is often unpredictable. This Perspective provides an overview of the recent developments of deuteration, with a focus on deuterated clinical candidates, and highlights both opportunities and challenges of this strategy.
在过去几年中，氘代在药物化学中的应用呈爆炸式增长，美国食品和药物管理局最近批准了首个氘代药物。精准氘代不仅仅是简单地改善药物的药代动力学参数，在面对代谢介导的毒性、药物相互作用和低生物转化等问题时，它可能会提供一个机会。氘代的应用范围更广，它提供了降低差向异构化程度、减少共给药增强剂剂量以及发现以氘代作为作用机制基础的化合物的机会。然而，设计、合成和开发成功的氘代药物远非易事，从概念到实践的转化往往是不可预测的。本文观点概述了氘代的最新发展，重点介绍了氘代临床候选药物，并强调了该策略的机遇和挑战。
