Since the FDA approved the steroid fludrocortisone, the first fluorine-containing drug, in 1955, the number of fluorine-containing drugs appearing on the market has rapidly risen to approximately 25% of drugs.1 These include the blockbuster drugs Prozac, Lipitor and Prevacid, Fig. 1. This may seem like an unusual trend considering fluorine-containing natural products are quite rare, so why is it that fluorine is so abundant in drugs? When you consider the unique chemical properties that fluorine has, the reason for a drug designer’s love of fluorine becomes clearer.
Fig. 1: Examples of fluorine-containing drugs
Fluorine is a small, highly electronegative and lipophilic atom. The incorporation of fluorine into a molecule is an increasingly popular strategy to improve drug potency. Fluorine substitution can enhance potency and impact target selectivity by affecting pKa, modulating conformation, hydrophobic interactions and lipophilicity. Fluorine is also frequently used to improve drug metabolism. More recently, radiolabelled fluorine drugs have been used in positron emission tomography (PET) for imaging and diagnosis purposes in medicine.2
Fig. 2: Effects of fluorine in medicinal chemistry3
Fluorine is much more lipophilic than hydrogen, so incorporating fluorine atoms in a molecule will often make it more fat soluble. This means permeability across membranes is increased resulting in a higher bioavailability. Because of the strong electron withdrawing ability of fluorine, it’s inclusion in a molecule has a very strong effect on the acidity or basicity of proximal functional groups. Altering the pKa can strongly modify the binding affinity and the pharmacokinetic properties of a pharmaceutical agent. Often, fluorine is introduced to lower the basicity of a compound which aids in permeability.4
Fluorine can play an important and unique role in influencing molecular conformation. Sterically, fluorine is similar in size to a hydrogen atom, but the high electronegativity of fluorine results in a highly polarised C-F bond with a strong dipole moment and a low-lying C-F anti-bonding orbital available for hyperconjugative donation.2 This can cause fluorine-containing molecules to adopt a different preferential conformation compared to the non-fluorinated molecule which may result in increased binding affinity to a receptor.
One of the major challenges in drug discovery is that of low metabolic stability of compounds. Lipophilic compounds are susceptible to oxidation by liver enzymes, in particular cytochrome P450. Fluorine substitution at the metabolically labile site or at adjacent sites to the site of metabolic attack is a common strategy to improve metabolic stability. The inductive effect of fluorine should result in decreased susceptibility of adjacent groups to metabolic attack by cytochrome P450. Additionally, fluorine can modulate lipophilicity and restrict conformation, which may afford improved metabolic stability.3
PET imaging using 18F tracers is a rapidly developing area in medicinal chemistry. PET scans show biological processes which can give invaluable metabolic information. PET is used as a diagnostic tool, particularly in oncology, but also as an in vivo pharmacological imaging tool in drug development, especially in the areas of biodistribution and drug occupancy studies.4
One drawback of introducing fluorine substituents into drugs is that fluorination can be rather difficult and many processes create challenges in the manufacturing process. However, numerous new, safe and mild fluorinating reagents have been invented in recent years, many of which are commercially available, making the process much simpler.5,6
Blog written by Catherine Tighe
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