Utilization of fluorinated α-amino acids in small molecule drug design

Fluorinated amino acids (FAAs) are at a focal point of two key current strategic areas within drug discovery being both important for the design/development of new small molecule drugs as well as having the potential to be exploited in the rapidly expanding area of peptide-based therapeutics. Their exquisite modularity, synthetic versatility, and extensive commercial availability coupled with the robust understanding of the roles that fluorine can play, and which improves their potency and physicochemical properties of drug candidates, have enabled FAAs to be widely used in numerous drug discovery programs.

This review provides an overview of the use of fluorinated amino acids in small drug discovery focusing initially on their impact across a diverse range of therapeutic areas before evaluating methods to access them synthetically. Furthermore, in-depth analyses of programs focusing on the design of thrombin, γ-secretase, and FXII inhibitors demonstrate how the strategic introduction of a specific fluorinated amino acid within a molecule can significantly favorably modulate the efficacy and/or the physicochemical properties of the lead through enhancing the electronic/steric interactions with the desired biological target.

While significant advances have been made enabling access to a broad range of fluorinated amino acids and their derivatives, there are several active ongoing research areas in this space. These most notably include developing methods for the synthesis of more-constrained fluorinated bicyclic amino acid derivatives potentially as bioisosteric replacements of aromatic moieties to increase the 3D-dimensionality of a compound while retaining both conformational rigidity and defined orientation of the functional vectors.