Quantitative Assessment of the Impact of Fluorine Substitution on P‑Glycoprotein (P-gp) Mediated Efflux, Permeability, Lipophilicity, and Metabolic Stability

• Published in: Journal of medicinal chemistry Vol. 59; no. 11; pp. 5284 - 5296
• Main Authors: Pettersson, Martin, Hou, Xinjun, Kuhn, Max, Wager, Travis T, Kauffman, Gregory W, Verhoest, Patrick R
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 09.06.2016
• Subjects: ATP-Binding Cassette, Sub-Family B, Member 1 - chemistry; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Fluorine - chemistry; Fluorine - metabolism; Hydrophobic and Hydrophilic Interactions; Molecular Structure; Molecular Weight; Permeability
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.6b00027

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 pK a. 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.