Analysis of Past and Present Synthetic Methodologies on Medicinal Chemistry: Where Have All the New Reactions Gone?
Analysis of Past and Present Synthetic Methodologies on Medicinal Chemistry: Where Have All the New Reactions Gone?
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DOI：
10.1021/acs.jmedchem.5b01409
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发表时间：
2016-05-26
影响因子：
7.3
通讯作者：
Bostrom, Jonas
中科院分区：
文献类型：
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作者：
Brow, Dean G.;Bostrom, Jonas
对当前药物化学（2014年）、三十年前（1984年）所使用的化学反应以及天然产物全合成进行了分析。分析表明，在当前最常用的合成反应中，没有一个是在过去20年内发现的，在20世纪80年代和90年代也仅有两个（铃木 - 宫浦反应和布赫瓦尔德 - 哈特维希反应）。这表明在药物研发中，新的合成反应要产生影响存在着内在的高门槛。最常用的反应是酰胺键形成、铃木 - 宫浦偶联反应和芳香族亲核取代反应，这很可能是由于试剂的商业可得性、高化学选择性以及交付压力。我们通过简单的PMI图表明，这些做法导致某些类型的分子形状过多，而其他形状则被排除在外。我们希望这些结果将有助于促进新合成方法的整合以及新化合物库设计的改进。
An analysis of chemical reactions used in current medicinal chemistry (2014), three decades ago (1984), and in natural product total synthesis has been conducted. The analysis revealed that of the current most frequently used synthetic reactions, none were discovered within the past 20 years and only two in the 1980s and 1990s (Suzuki-Miyaura and Buchwald-Hartwig). This suggests an inherent high bar of impact for new synthetic reactions in drug discovery. The most frequently used reactions were amide bond formation, Suzuki-Miyaura coupling, and SNAr reactions, most likely due to commercial availability of reagents, high chemoselectivity, and a pressure on delivery. We show that these practices result in overpopulation of certain types of molecular shapes to the exclusion of others using simple PMI plots. We hope that these results will help catalyze improvements in integration of new synthetic methodologies as well as new library design.