Fluorine in Drug Discovery

The importance of Fluorine in medicinal chemistry is well recognized. Indeed, an increasing number of drugs on the market contain Fluorine, the presence which often is of major importance to activity. A recent review article (Chem. Soc. Rev., 2008, 37, 320) by Sophie Purser describes the role of Fluorine in medicinal chemistry.

Replacement of hydrogen with Fluorine (F) in a pharmacologically active molecule can profoundly change the conformational preference due to its size difference and stereoelectronic effects.

1) F can enhance binding efficacy and selectivity in pharmaceuticals.

2) F substituents on ligands prefer to orient toward electropositive regions of receptor sites.

3) Distinct fluorofilic environment in proteins includes the ubiquitous peptide bonds, which undergo multipolar C-F…H-N, C-F..C=O and C-F..H-C interaction.

Systematic fluorine scans of ligands is a promising strategy during the lead optimization stage of drug discovery. Fluorine substitution enhances physicochemical and adsorption, distribution, metabolism, and excretion properties and strengthens protein-ligand binding interaction.

The effects of Fluorine substitution expands, further applications in drug discovery will emerge. 

Modern fluorine organic chemistry has dramatically widened the synthetic repertoire for the specific introduction of Fluorine in an organic molecule.