The Important Impact of Fluorine in Pharmaceuticals

Fluorine has become an essential tool in drug discovery. Including fluorine atoms in potential medicines can have a variety of dramatic effects on the molecules' properties, perhaps making them more selective, increasing their efficacy, or making them easier to administer. So it is no great surprise that around a fifth of all drugs on the market today contain at least one fluorine substituent. Indeed, three of the current top ten best sellers contain fluorine atoms, including the biggest blockbuster medicine, Pfizer's lipid lowering agent Lipitor (atorvastatin), which has an aromatic fluorine substituent. TAP's proton pump inhibitor Prevacid (lansoprazole) includes a difluoromethylene unit. And the fluticasone component of GlaxoSmithKline's antiasthma combination product Seretide has no less than three separate fluorine substituents. There are very few naturally occurring organic compounds that contain fluorine, so it may seem a little odd that the element has become such a key component in the drug design process. Free fluoride ions are much, much less abundant in nature than chloride ions, and as a result bacteria tend to incorporate other halogens, particularly chloride, instead. But when one considers its chemical properties, the reason for the drug designer's enduring love of fluorine becomes much clearer. Drug designers frequently use naturally occurring molecules as starting points in their studies, altering substitution patterns to change its properties to make it more effective, more selective, or both. And fluorine can make some very big differences. Its high electronegativity means it has a large electronic effect at neighbouring carbon centres, as well as having a substantial effect on the molecule's dipole moment, the acidity or basicity of other groups nearby, not to mention the molecule's overall reactivity and stability. It also means the fluorine centre can act as a hydrogen bond acceptor, and its three non-bonded pairs of electrons even enable it to act as a ligand for alkali metals. Despite the fact that the fluoride atom is larger than hydrogen, the additional steric demand caused by replacing an H with an F at receptor sites on cells or enzymes is low. 1 The carbon-fluorine bond length is not that much greater than carbon-hydrogen, either, so the switch causes little change to the steric bulk of the molecule. Although a carbon-fluorine bond is somewhat stronger than other carbon-halogen bonds, fluorine is still a better leaving group than hydrogen, so there is some potential for covalent bonds to be formed between the …