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Review
. 2020 Apr 22;5(19):10633-10640.
doi: 10.1021/acsomega.0c00830. eCollection 2020 May 19.

Contribution of Organofluorine Compounds to Pharmaceuticals

Munenori Inoue  1 , Yuji Sumii  2 , Norio Shibata  2   3
Affiliations
Review

Contribution of Organofluorine Compounds to Pharmaceuticals

Munenori Inoue et al. ACS Omega. .

Abstract

Inspired by the success of fluorinated corticosteroids in the 1950s and fluoroquinolones in the 1980s, fluorine-containing pharmaceuticals, which are also known as fluoro-pharmaceuticals, have been attracting attention for more than half of a century. Presently, about 20% of the commercial pharmaceuticals are fluoro-pharmaceuticals. In this mini-review, we analyze the prevalence of fluoro-pharmaceuticals in the market and categorize them into several groups based on the chemotype of the fluoro-functional groups, their therapeutic purpose, and the presence of heterocycles and/or chirality to highlight the structural motifs, patterns, and promising trends in fluorine-based drug design. Our database contains 340 fluoro-pharmaceuticals, from the first fluoro-pharmaceutical, Florinef, to the latest fluoro-pharmaceuticals registered in 2019 and drugs that have been withdrawn. The names and chemical structures of all the 340 fluorinated drugs discussed are provided in the Supporting Information.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Selected landmark fluoro-pharmaceuticals: Forinef acetate, levofloxacin, and Lipitor.
Figure 2
Figure 2
17 fluoro-pharmaceuticals globally registered in 2019 including one fluorinated-biologic drug, trastuzumab deruxtecan. The 14 fluoro-pharmaceuticals indicated with blue color are approval by the FDA. Akynzeo was excluded since the active ingredient of akynzeo is fosnetupitant, which was approved in 2014 by the FDA. Elexacaftor is one of the active ingredients of trikafta, which contains another fluoro-pharmaceutical, tezacaftor.
Figure 3
Figure 3
(a) Prevalence of fluoro-pharmaceuticals among globally registered drugs (1991–2019). The list of the all pharmaceuticals (1072 compounds), small-molecule drugs (839 compounds), and fluoro-pharmaceuticals (191 compounds) is provided (Table S2). (b) Data for small-molecule drugs over the past five years.
Figure 4
Figure 4
Chemotype distribution of fluoro-pharmaceuticals.
Figure 5
Figure 5
Disease-focused classification of fluoro-pharmaceuticals according to the Anatomical Therapeutic Chemical Classification (ATC) of the WHO. A: Gastrointestinal and metabolism action. B: Blood and hematopoietic organ. C: Circulatory system. D: Skin disease remedy. G: Urogenital system and sex hormone. H: General hormonal drug. J01: General antimicrobial. J02: General antifungal. J04: Antimycobacteria. J05: General antiviral. L01: Antitumor drug (molecularly targeted agents (MTAs)). L01: Antitumor drug (without MTAs). L04: Immunosuppressive agent. M01: Nonsteroidal anti-inflammatory drugs (NSAID). M09: Musculoskeletal system agents. N01: Anesthetics. N02: Antipyretic analgesics. N03: Antiepileptic drug. N04: Antiparkinson agent. N05A: Antipsychotic agent. N05B: Antianxiety agent. N05C: Hypnotic drug. N06: Antidepressant drug. N07: Nervous system agent. P: Anthelmintics. R: Respiratory disease agent. S: Sensory system disease agent. V: Others.
Figure 6
Figure 6
Fluoro-functionalized heterocycles in fluoro-pharmaceuticals (42 drugs with 43 chemo-type functional groups; gemigliptin contains two fluoro-functionalized heterocyclic fragments).
Figure 7
Figure 7
Selected examples of fluoro-functionalized heterocycles in fluoro-pharmaceuticals: (a) CHet–F and (b) CHet–CF3. A full list of F-heterocycles is provided in Figure S2.
Figure 8
Figure 8
Chirality in fluoro-pharmaceuticals. (a) Enantiomers of thalidomide and (b) the fluorinated isosteres of fluorothalidomide.
Figure 9
Figure 9
Selected fluoro-pharmaceuticals with a fluorine or fluoro-functional group at a stereogenic carbon center, including racemic compounds (see Figure S3 in the SI for the full list).
See this image and copyright information in PMC

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