Revolutionizing Therapeutics: The Transformative Power of Fluorinated Compounds

The role of fluorinated compounds is becoming increasingly critical in the evolving pharmaceutical landscape. In 2020, the U.S. Food and Drug Administration (FDA) approved 13 compelling new fluorinated drugs, each of which represents a significant advancement in their respective therapeutic areas. These breakthrough approvals highlight the transformative potential of fluorinated compounds in drug development.

From the treatment of Cushing's disease and neurofibromas to the treatment of migraines, Alzheimer's disease, myelodysplastic syndromes, hereditary angioedema episodes, and a variety of cancers, these fluorinated medications have proven their versatility and efficacy.

The 13 new fluorinated drugs approved by the FDA include Ayvakit^®, Isturisa^®, Koselugo^®, Pemazyre^®, Tabecta^®, Qinlock^®, Nurtec ODT^®, Cerianna^®, Tauvid^®, Inqovi^®, Pralsebinib^®, Orladeyo^®, and Orgovyx^®. These drug molecules contain a variety of fluorinated functional groups, including aromatic fluorine (Ar-F), aromatic Ar-CF3, aliphatic CHF, and CF2 groups. These structural features confer enhanced pharmacological properties to the new drugs, such as improved metabolic stability, increased potency, and enhanced target selectivity.

Fig.1 Molecules of these approved drugs feature aromatic fluorine (Ar-F) (11 compounds), aromatic Ar-CF3 (1), aliphatic CHF (1) and CF2 (1) groups.^[1]

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Common Fluorination Strategies

Incorporation of the above-fluorinated portions into drug structures is a strategic approach used by pharmaceutical researchers and chemists to enhance the pharmacological properties of compounds. Fluorine substitution can be achieved through a variety of synthetic methods and fluorination strategies that allow for the selective introduction of fluorine atoms at specific locations within the drug scaffold.

Some of the common fluorination techniques used in drug development include:

• Nucleophilic Fluorination: this method involves the replacement of a leaving group (e.g., halide, sulfonyl, or hydroxyl) with a fluoride source (e.g., potassium fluoride or sodium fluoride) under appropriate reaction conditions.
• Electrophilic Fluorination: In this method, an electrophilic fluorinating agent, such as N-fluorobenzenesulfonimide (NFSI) or Selectflor^®, is used to introduce fluorine atoms directly onto the target molecule.
• Transition Metal-mediated Fluorination: The use of transition metal catalysts (e.g., palladium or copper) can facilitate the incorporation of fluorine atoms through cross-coupling reactions or other fluorination schemes.
• Fluorinated Decarboxylation: This strategy involves the replacement of the carboxyl group with a fluorine atom and is typically achieved through the use of reagents such as DAST (diethylamino sulfur trifluoride) or Deoxo-Fluor^®.

By strategically employing these fluorination techniques, medicinal chemists can tailor the physicochemical and pharmacokinetic properties of drug molecules to improve metabolic stability, increase potency, enhance target selectivity, and ultimately achieve better therapeutic outcomes.

The incorporation of fluorinated functional groups can also affect a drug's lipophilicity, hydrogen bonding ability, and overall conformation, all of which help optimize a compound's pharmacological profile.

Fig.2 Examples of safe and selective fluorination agents. (A) Nucleophilic agents, (B) electrophilic agents, and (C) reagents to introduce CF3 groups.^[2]

The recent approval of fluorinated drugs by the FDA is a testament to the transformative power of fluorination in the pharmaceutical industry. Going forward, the continued advancement of fluoride in the pharmaceutical industry promises to usher in a new era of personalized and targeted therapies. By strategically integrating these fluorinated components into drug molecules, researchers and clinicians can unlock the unprecedented therapeutic potential to address unmet medical needs and improve the quality of life for patients worldwide.

References

1. Yu Y, et al. (2021). "Fluorine-containing Pharmaceuticals Approved by The FDA in 2020: Synthesis and Biological Activity." International journal of Environmental Science and Technology, 32(11), 3342-3354.
2. Müller K, et al. (2007). "Fluorine in Pharmaceuticals: Looking Beyond Intuition." Science, 317, 1881.