Quantitative Assessment of the Impact of Fluorine Substitution on P-Glycoprotein (P-Gp) Mediated Efflux, Permeability, Lipophilicity, and Metabolic Stability
Pettersson M, Hou X, Kuhn M, Wager TT, Kauffman GW, Verhoest PR (2016). “Quantitative assessment of the impact of fluorine substitution on P-glycoprotein (P-gp) mediated efflux, permeability, lipophilicity, and metabolic stability.” Journal of medicinal chemistry, 59(11), 5284-5296.
Abstract
Strategic replacement of one or more hydrogen atoms with fluorine atom(s) is a common tactic to improve potency at a given target and/or to modulate parameters such as metabolic stability and pKa. Molecular weight (MW) is a key parameter in design, and incorporation of fluorine is associated with a disproportionate increase in MW considering the van der Waals radius of fluorine versus hydrogen. Herein we examine a large compound data set to understand the effect of introducing fluorine on the risk of encountering P-glycoprotein mediated efflux (as measured by MDR efflux ratio), passive permeability, lipophilicity, and metabolic stability. Statistical modeling of the MDR ER data demonstrated that an increase in MW as a result of introducing fluorine atoms does not lead to higher risk of P-gp mediated efflux. Fluorine-corrected molecular weight (MWFC), where the molecular weight of fluorine has been subtracted, was found to be a more relevant descriptor.