Pharmaceutical Applications of Organofluorine Compounds. ¹⁹ F NMR Fragment‐Based Discovery

Abstract The selective introduction of the small and highly electronegative fluorine atom is a well‐established strategy in medicinal chemistry. Its ability to modulate key molecular physicochemical parameters leads to improved pharmacokinetic properties such as metabolic stability and permeability. Furthermore, the fluorine atom is able to modulate molecular conformation, and it has been widely used to enhance the binding affinity to targets. On the other side, its incorporation can convey chemical instability, which may lead to molecular cleavage by drug‐metabolizing enzymes and potential safety issues. The utilization of 19 F NMR‐based screening for the search of novel hits is now widely extended, either with methods that use 19 F‐labeled small molecules (FAXS and n‐FABS) or the incorporation of fluorine in the target of interest (PrOF NMR). This chapter aims to discuss relevant applications of fluorine in medicinal chemistry and 19 F NMR, summarizing the most applied strategies and citing selected examples of fluorine‐containing pharmaceuticals.