Lessons learned from marketed and investigational prodrugs.
Lessons learned from marketed and investigational prodrugs.
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DOI：
10.1002/chin.200430295
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发表时间：
2004-05
影响因子：
7.3
通讯作者：
P. Ettmayer;G. Amidon;B. Clement;B. Testa
中科院分区：
文献类型：
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作者：
P. Ettmayer;G. Amidon;B. Clement;B. Testa
前药是克服药物有用性障碍的既定概念。在德国，所有上市药物中约有6.9%可归类为前药，这是基于保守的前药定义（不包括软药和有限的前药）的估计。有限前药（估计占德国市售药物的4%）定义为其代谢产物也有助于观察到的治疗活性的活性药物。大约49%的市售前药是通过水解活化的，23%是通过生物合成反应活化的生物前体（即缺乏前体）。1值得注意的重磅炸弹前药是，例如，奥美拉唑，辛伐他汀，洛伐他汀，依那普利和阿昔洛韦（图1）。监管指南对前药特有的问题关注有限。2因此，从前药发展的活性药物被认为是活性代谢物。在药物化学中，前药策略实际上从未在药物设计的早期阶段被考虑，而是只有当经典的模拟程序不能提供所需的药物特征时才被考虑。那么，是什么使前药开发如此特别和有趣呢？前药提供了达到目标理化、药代动力学和药效学特性的原理和机会。它们可以被设计为克服药物、药代动力学或药效学障碍，例如化学稳定性不足、溶解性差、不可接受的味道或气味、刺激或疼痛、口服吸收不足、血脑屏障渗透性不足、明显的系统前代谢和毒性。一个高度重要的发展领域是合理设计用于组织或细胞靶向的前药。然而，值得回顾的是，目前使用的许多成功的前药实际上是偶然的前药，即，未被设计为前药并且仅在开发后期或甚至上市后才被认为是前药的药剂。本文旨在为早期的
Prodrugs are an established concept to overcome barriers to a drug’s usefulness. In Germany, about 6.9% of all marketed medicines can be classified as prodrugs, an estimate based on a conservative prodrug definition that does not include soft drugs and limited prodrugs. The limited prodrugs, which comprise an estimated 4% of the medicines marketed in Germany, are defined as active agents whose metabolite (s) also contribute (s) to the observed therapeutic activity. Approximately 49% of all marketed prodrugs are activated by hydrolysis, and 23% are bioprecursors (ie, lacking a promoiety) activated by a biosynthetic reaction. 1 Noteworthy blockbuster prodrugs are, for example, omeprazole, simvastatin, lovastatin, enalapril, and aciclovir (Figure 1). Regulatory guidelines pay limited attention to issues specific to prodrugs. 2 Thus, active drugs developed from prodrugs are considered as active metabolites. In medicinal chemistry, a prodrug strategy is practically never considered in the early phases of drug design but only when classical analoguing programs fail to provide the required drug profile. What, then, makes prodrug development so special and interesting? Prodrugs provide a rationale and opportunities to reach target physicochemical, pharmacokinetic, and pharmacodynamic properties. They can be designed to overcome pharmaceutical, pharmacokinetic, or pharmacodynamic barriers such as insufficient chemical stability, poor solubility, unacceptable taste or odor, irritation or pain, insufficient oral absorption, inadequate blood-brain barrier permeability, marked presystemic metabolism, and toxicity. 3 A developing field of high importance is that of rationally designed prodrugs for tissue or cell targeting. However, it is worth recalling that many successful prodrugs in current use are in fact accidental prodrugs, namely, agents that were not designed as prodrugs and were recognized as such only late in development or even postmarketing. This article intends to provide some arguments and guidelines for the early