Synopsis of Some Recent Tactical Application of Bioisosteres in Drug Design
Synopsis of Some Recent Tactical Application of Bioisosteres in Drug Design
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DOI：
10.1021/jm1013693
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发表时间：
2011-04-28
影响因子：
7.3
通讯作者：
Meanwell, Nicholas A.
中科院分区：
文献类型：
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作者：
Meanwell, Nicholas A.
相对简单的化学实体之间的电子等排的概念最初是由詹姆斯·莫尔在1909年提出的，这个概念被HG·格里姆的氢化物置换定律进一步完善，并在欧文·朗缪尔基于实验观察提出的想法中得到了更有效的体现。1-3朗缪尔创造了“电子等排体”一词，并在实际分离和表征之前18年预测，当时未知的乙烯酮的物理性质与重氮甲烷相似。[3]生物电子等排体是一种结构独特的化合物，被生物系统识别为相似的化合物，它的出现起源于20世纪30年代Hans Erlenmeyer发表的一系列研究，他扩展了Karl Landsteiner的早期工作。Erlenmeyer表明，在通过重氮离子与蛋白质反应衍生的人工抗原的情况下，抗体不能区分苯环和噻吩环或O、NH和CH 2，这是一种衍生酪氨酸邻位的过程，如图11、2、4所示，[5]生物电子等排体一词由哈里斯·弗里德曼于1950年提出，他将其定义为引起类似生物效应的化合物，同时认识到化合物可能是电子等排体，但不一定是生物电子等排体。6这一概念预计生物电子等排的应用将取决于背景，而不是依赖物理化学性质作为生化模拟的基本原则。生物电子等排体通常比精确的结构模拟物更少，并且通常在生物学性质而不是物理性质上更相似。因此，一种生物化学应用的有效生物电子等排体可能无法转化为另一种环境，需要针对特定情况仔细选择和调整电子等排体。因此，生物电子等排体的设计经常引入结构变化，这些结构变化可以是有益的或有害的，这取决于上下文，其中大小、形状、电子分布、极化率、偶极、极性、亲油性和pKa在分子识别和模拟中可能起关键作用。在药物化学的当代实践中，生物电子等排体的开发和应用已被采用作为一种基本的战术方法，可用于解决与候选药物的设计和开发相关的许多方面。1，2，7-13生物电子等排体的既定用途在本质上是广泛的，延伸到提高效力、增强选择性、改变物理性质、减少或重定向代谢、消除或修饰毒力载体以及获得新的知识产权。在这个角度来看，一些当代的主题探索等排体在药物设计中的作用进行了抽样，重点放在战术应用，旨在解决各种问题，影响化合物优化和候选药物的长期成功。有趣的概念，可能已经在审查的情况下效果不佳的捕获，因为这些想法可能有价值的替代情况。生物电子等排体的全面编目超出了将提供的范围，尽管在几个部分中以简洁的方式概述了特定功能的相关电子等排体的概要。电子等排现象也在有机催化剂的设计和优化中得到了有效的应用，并且有几个例子表明，最初在药物化学环境中建立的功能模拟已经被该社区采用。14
The concept of isosterism between relatively simple chemical entities was originally contemplated by James Moir in 1909, a notion further refined by HG Grimm’s hydride displacement law and captured more effectively in the ideas advanced by Irving Langmuir based on experimental observations. 1-3 Langmuir coined the term “isostere” and, 18 years in advance of its actual isolation and characterization, predicted that the physical properties of the then unknown ketene would resemble those of diazomethane. 3 The emergence of bioisosteres as structurally distinct compounds recognized similarly by biological systems has its origins in a series of studies published by Hans Erlenmeyer in the 1930s, who extended earlier work conducted by Karl Landsteiner. Erlenmeyer showed that antibodies were unable to discriminate between phenyl and thienyl rings or O, NH, and CH2 in the context of artificial antigens derived by reacting diazonium ions with proteins, a process that derivatized the ortho position of tyrosine, as summarized in Figure 11, 2, 4, 5 The term “bioisostere” was introduced by Harris Friedman in 1950 who defined it as compounds eliciting a similar biological effect while recognizing that compounds may be isosteric but not necessarily bioisosteric. 6 This notion anticipates that the application of bioisosterism will depend on context, relying much less on physicochemical properties as the underlying principle for biochemical mimicry. Bioisosteres are typically less than exact structural mimetics and are often more alike in biological rather than physical properties. Thus, an effective bioisostere for one biochemical application may not translate to another setting, necessitating the careful selection and tailoring of an isostere for a specific circumstance. Consequently, the design of bioisosteres frequently introduces structural changes that can be beneficial or deleterious depending on the context, with size, shape, electronic distribution, polarizability, dipole, polarity, lipophilicity, and pKa potentially playing key contributing roles in molecular recognition and mimicry. In the contemporary practice of medicinal chemistry, the development and application of bioisosteres have been adopted as a fundamental tactical approach useful to address a number of aspects associated with the design and development of drug candidates. 1, 2, 7-13 The established utility of bioisosteres is broad in nature, extending to improving potency, enhancing selectivity, altering physical properties, reducing or redirecting metabolism, eliminating or modifying toxicophores, and acquiring novel intellectual property. In this Perspective, some contemporary themes exploring the role of isosteres in drug design are sampled, with an emphasis placed on tactical applications designed to solve the kinds of problems that impinge on compound optimization and the long-term success of drug candidates. Interesting concepts that may have been poorly effective in the context examined are captured, since the ideas may have merit in alternative circumstances. A comprehensive cataloging of bioisosteres is beyond the scope of what will be provided, although a synopsis of relevant isosteres of a particular functionality is summarized in a succinct fashion in several sections. Isosterism has also found productive application in the design and optimization of organocatalysts, and there are several examples in which functional mimicry established initially in a medicinal chemistry setting has been adopted by this community. 14