title: Quantitative Assessment of the Impact of Fluorine Substitution on P-Glycoprotein (P-gp) Mediated Efflux, Permeability, Lipophilicity, and Metabolic Stability.
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.
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development , Cambridge, Massachusetts 02139, United States.
authors.forename: Martin
authors.initials: M
authors.lastname: Pettersson
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development , Cambridge, Massachusetts 02139, United States.
authors.forename: Xinjun
authors.initials: X
authors.lastname: Hou
authors.affiliation: Research Statistics, Pfizer Worldwide Research and Development , Groton, Connecticut 06340, United States.
authors.forename: Max
authors.initials: M
authors.lastname: Kuhn
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development , Cambridge, Massachusetts 02139, United States.
authors.forename: Travis T
authors.initials: TT
authors.lastname: Wager
authors.affiliation: Computational ADME Group, Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research and Development , Groton, Connecticut 06340, United States.
authors.forename: Gregory W
authors.initials: GW
authors.lastname: Kauffman
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development , Cambridge, Massachusetts 02139, United States.
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Verhoest
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000737:chemistry* / Q000378:metabolism*; D005461:Fluorine / Q000737:chemistry* / Q000378:metabolism*; D057927:Hydrophobic and Hydrophilic Interactions; D015394:Molecular Structure; D008970:Molecular Weight; D010539:Permeability
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D005461:Fluorine