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手性药物市场:手性转换与从头获得的对映纯化合物。

The market of chiral drugs: Chiral switches versus de novo enantiomerically pure compounds.

机构信息

Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, P.le Aldo Moro 5, 00185 Roma, Italy.

Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, P.le Aldo Moro 5, 00185 Roma, Italy.

出版信息

J Pharm Biomed Anal. 2018 Jan 5;147:323-340. doi: 10.1016/j.jpba.2017.07.008. Epub 2017 Jul 10.

Abstract

This review article is aimed at providing an overview of the current market of chiral drugs by exploring which is the nowadays tendency, for the pharmaceutical industry, either to exploit the chiral switching practice from already marketed racemates or to develop de novo enantiomerically pure compounds. A concise illustration of the main techniques developed to assess the absolute configuration (AC) and enantiomeric purity of chiral drugs has been given, where greater emphasis was placed on the contribution of enantioselective chromatography (HPLC, SFC and UHPC). Afterwards, we focused our study on the cohort of 45 new drugs that have been approved by the US Food and Drug Administration (FDA) in 2015. We extracted the chemical structure of the new drugs from the FDA approval chemistry reviews available on the database of the agency's Center for Drug Evaluation and Research (CDER), and we selected a subgroup (i.e., 44% of the cohort) of small-molecule active pharmaceutical ingredients (APIs) containing one or more chirality centers. On the basis of the FDA dossiers examined, it emerged that all the chiral drugs approved by the FDA in 2015 are enantiomerically pure compounds with a well-defined AC, with the exception of one, namely lesinurad, which has been licensed as the racemate of two enantiomeric atropoisomers, arising because of the hindered rotation around the single C-N bond in the naphthalene ring. Finally, none of the previously developed racemates has been switched to the single-enantiomer version in 2015.

摘要

这篇综述文章旨在探讨制药行业目前的趋势,即是利用已上市的外消旋体的手性转换实践,还是开发新的对映体纯化合物,从而对当前的手性药物市场进行概述。本文简要介绍了评估手性药物的绝对构型(AC)和对映体纯度的主要技术,其中重点介绍了对映选择性色谱(HPLC、SFC 和 UHPC)的贡献。之后,我们将研究重点放在了 2015 年美国食品和药物管理局(FDA)批准的 45 种新药上。我们从该机构药物评估和研究中心(CDER)数据库中的 FDA 批准化学评论中提取了新药的化学结构,并选择了一个小分子活性药物成分(API)亚组(即队列的 44%),其中包含一个或多个手性中心。根据检查的 FDA 档案,2015 年 FDA 批准的所有手性药物都是具有明确 AC 的对映体纯化合物,只有一种药物(即 lesinurad)是萘环中单键 C-N 旋转受阻而产生的两种对映体(atropoisomers)的外消旋体。最后,2015 年没有一种已开发的外消旋体被转换为单一的对映异构体版本。

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