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J Med Chem. 2016 May 26;59(10):4443-58. doi: 10.1021/acs.jmedchem.5b01409. Epub 2015 Dec 1.

Analysis of Past and Present Synthetic Methodologies on Medicinal Chemistry: Where Have All the New Reactions Gone?

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AstraZeneca Neurosciences, IMED Biotech Unit, AstraZeneca R&D Boston , 141 Portland Street, Cambridge, Massachusetts 02139, United States.
CVMD Innovative Medicines, IMED Biotech Unit, AstraZeneca , Mölndal SE-431 83, Sweden.


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.

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