Eric P. Gillis

Applications of Fluorine in Medicinal Chemistry

The role of fluorine in drug design and development is expanding rapidly as we learn more about the unique properties associated with this unusual element and how to deploy it with greater sophistication. The judicious introduction of fluorine into a molecule can productively influence conformation, pKa, intrinsic potency, membrane permeability, metabolic pathways, and pharmacokinetic properties. In addition, (18)F has been established as a useful positron emitting isotope for use with in vivo imaging technology that potentially has extensive application in drug discovery and development, often limited only by convenient synthetic accessibility to labeled compounds. The wide ranging applications of fluorine in drug design are providing a strong stimulus for the development of new synthetic methodologies that allow more facile access to a wide range of fluorinated compounds. In this review, we provide an update on the effects of the strategic incorporation of fluorine in drug molecules and applications in positron emission tomography.

Tactical Applications of Fluorine in Drug Design and Development

The increasing utilization of fluorine in drug design parallels advances in understanding the physicochemical attributes of this element and an enhanced appreciation of how these unique properties can be exploited to address the numerous challenges encountered in pharmaceutical candidate optimization. Judicious placement of fluorine in a candidate compound can markedly affect potency, increase metabolic stability and enhance membrane permeability. The powerful electron-withdrawing nature of fluorine serves to modulate the pKa of proximal functionality, particularly basic amines, and can be an important tool for controlling physical properties. Fluorine also exerts a conformation bias that is significant and can be utilized strategically. The 18F isotope is of particular importance in positron emitting tomography (PET), an imaging technique of increasing importance for assessing drug-target engagement in both preclinical and clinical settings. This chapter provides a synopsis of some of the prominent and emerging applications of fluorine in the design and optimization of biologically active molecules.