Reasons and Status of Organofluorine Compounds As Drugs

Introduction

Fluorine-containing pharmaceuticals have been attracting attention for more than half of a century. And, more and more fluorine-containing pharmaceuticals have entered the market to treat different diseases in recent years. For example, in 2018, 38 small-molecule pharmaceuticals were approved by the U.S. Food and Drug Administration (FDA), of which 17 (45%) were fluoro-pharmaceuticals^[1]. At present, approximately 20% of pharmaceuticals marketed are organofluorine compounds. There seems to be a strong belief in the minds of researchers that by introducing fluorine atoms into the organic molecule, the chances of obtaining better therapeutic compounds are increased. Based on this, Alfa Chemistry introduces the effect of fluorine on drugs, and introduces the situation of fluorinated drugs on the market from the perspective of the chemical type, therapeutic purpose and the presence of hybrids in order to explain the design structural motif, model and promising trend of organofluorine compounds as drug design, and thus contributing to the further development of organic fluorinated drugs.

Fig.1. Data for small-molecule drugs from 2015 to 2019.

The Effect of Fluorine on Drugs

The reason why organofluorine compounds are very popular in pharmaceuticals is due to the unique properties of fluorine atoms, which can bring great improvements to all aspects of drugs ^[2].

• The presence of fluorine has obvious influence on the pharmacokinetics and kinetic properties of pharmaceuticals. Because the C-F bond is very strong, and the presence of electronegative fluorine atoms also affects the strength of other bonds. Therefore, different enzymes are easier to survive for metabolism, thus prolonging the efficacy.
• The presence of fluorine can increase the lipophilicity of the pharmaceuticals. Pharmaceuticals need to be moderately lipophilic to pass easily through lipid membranes, and fluoridation is a better choice in most cases because of its high lipophilicity and increased drug absorption. Therefore, rational use of fluorine atoms in molecules can improve the lipophilicity of pharmaceuticals and thus increasing the bioavailability and potency of pharmaceuticals.
• In addition, the most important feature of introduction of fluorine atoms is their electronic effects that change the physicochemical properties. For example, the pKa value of a pharmaceutical can be easily adjusted by introducing fluorine atoms, thereby improving the bioavailability of pharmaceuticals containing amine functional groups.

The Situation of Fluorinated Pharmaceuticals

Inoue et al. analyzed a database of fluoro-pharmaceuticals registered between 1954 and 2019 contains more than 300 drugs, including fluoro-pharmaceuticals that have been withdrawn ^[1]. According to their report, we summarized the situation of fluorinated pharmaceuticals on the market based on the chemical type, therapeutic purpose and the presence of hybrids. The details are shown in below.

• The largest family of fluoro-pharmaceuticals is Ar−F-containing drugs, followed by molecules with alkyl−CRF, aryl−CF₃, Het−F, and Het-CF₃ groups. In addition, pharmaceuticals with monofluorinated moieties (Ar−F, alkyl−CRF, Het−F, alkyl−CH₂F) are most common, followed by drugs with trifluoromethyl groups (Ar−CF₃, Het−CF₃, alkyl−CF₃); these two categories comprise 86% of all fluoro-pharmaceuticals. Other fluoro-functional groups, including fluoroalkyl groups (CH₂F, CHF₂), fluorine-containing alkoxy groups (OCF₃, OCHF₂, OCH₂CF₃), fluorine-containing alkyl sulfides (SCH₂F, SCHF₂, SCH₂CF₃), and fluorine-containing alkylamino groups (NC(O)CF₃, NCH₂CH₂F, NCH₂CF₃), are also present in small amounts in the fluoro-pharmaceuticals family.

Fig.2 Chemotype distribution of fluoro-pharmaceuticals.

• Fluoro-pharmaceuticals have been used for a broad range of therapeutic purposes. The top fluorine-containing pharmaceuticals are: skin disease remedies (13.5%), general antifungal reagents (10.6%), antitumor drugs (molecularly targeted agents (MTAs)) (9.4%), gastrointestinal and metabolism agents (7.0%), and antipsychotic agents (6.7%).
• Heterocyclic compounds are commonly used as privileged fragments for drug discovery. More than 85% of biologically active compounds contain one or more heterocyclic fragments. Contrary to expectations, the number of pharmaceuticals with fluoro-functionalized heterocyclic fragments is relatively low, and their structural diversity is also highly limited. Of more than 300 fluoro-pharmaceuticals, only 42 contain fluoro-functionalized heterocyclic fragments, and the total number of fluoro-functionalized heterocyclic fragments is 43. These unexpected results could possibly be attributed to the relatively small variety of fluoro-functionalized heterocyclic compounds available.

Fig.3. Selected examples of fluoro-functionalized heterocycles in fluoro-pharmaceuticals.

It is believed that the article will give you some guidance and ideas for your research - you may have a clear idea of what structure is suitable for fluorinated pharmaceuticals development and what structure is suitable for which therapeutic purposes, etc. Of course, if you still need help in the development of fluorinated pharmaceuticals, Alfa Chemistry will be happy to help you, and we can offer you with fluorinated API development services. You can contact our engineers online and we will provide you with professional solution.

References

1. Inoue M, et al. Contribution of organofluorine compounds to pharmaceuticals[J]. ACS omega, 2020, 5(19): 10633-10640.
2. Chandra G., et al. Fluorine-a small magic bullet atom in the drug development: perspective to FDA approved and COVID-19 recommended drugs[J]. Chemical Papers, 2023: 1-22.