Reducing the Lipophilicity of Perfluoroalkyl Groups by CF₂–F/CF₂–Me or CF₃/CH₃ Exchange

Abstract

Fluorination is commonly employed to optimize bioactivity and pharmaco-kinetic properties of drug candidates. Aliphatic fluorination often reduces the lipophilicity (log P), but polyfluoroalkylation typically increases lipophilicity. Hence, identification of polyfluorinated motifs that nonetheless lead to similar or even reduced lipophilicities is of interest to expand the arsenal of medicinal chemistry tools in tackling properties such as compound metabolic stability or off-target selectivity. We show that changing a CF 3 -group of a perfluoroalkyl chain to a methyl group leads to a drastic reduction in lipophilicity. We also show that changing a C−F bond of a trifluoromethyl group, including when incorporated as part of a perfluoroalkyl group, to a C−Me group, leads to a reduction in log P, despite the resulting chain elongation. The observed lipophilicity trends were identified in fluorinated alkanol models and reproduced when incorporated in analogues of a drug candidate, and the metabolic stability of these motifs was demonstrated.

Systematic Investigation of Lipophilicity Modulation by Aliphatic Fluorination Motifs

“…The direct determination of logP values was conveniently achieved by a 19 F NMR based method developed by our group, which is suitable for measuring the octanol/water partition coefficients P of (fluorinated) non-UV active substrates. 31 The use of an internal standard as a mixture with the compound of interest obviates the need for accurate weight/partition volume/sample volume measurements. Potential quantitative integration issues due to the solvent-dependence of the relaxation time are minimized by selecting a sufficiently long relaxation delay for the NMR experiments (D1-setting).…”

Efficient Access to 3,5-Disubstituted 7-(Trifluoromethyl)pyrazolo[1,5-a]pyrimidines Involving SNAr and Suzuki Cross-Coupling Reactions

“…The 3-bromo-7-(trifluoromethyl) pyrazolo [1,5-a]pyrimidin-5-one 4 served as a building block for the synthesis of 3,5-disubstituted 7-(trifluoromethyl)pyrazolo [1,5-a] a]pyrimidine derivatives were found to have an antiviral effect against the respiratory syncytial virus (RSV) [21] and hepatitis C virus [22], and are inhibitors of phosphodiesterase (PDE) 2A [23] and 10A [24][25][26], promising new targets for the treatment of cognitive disorders and schizophrenia, respectively. The incorporation of a fluorine atom into potential pharmaceutical substances has been successfully used as a key strategy for enhancing the activity of drugs or drug candidates [27,28]. The introduction of fluorine atoms leads to a change in the solubility and lipophilicity of compounds, thus increasing their bioavailability and their cell membranes permeability.…”

“…The incorporation of a fluorine atom into potential pharmaceutical substances has been successfully used as a key strategy for enhancing the activity of drugs or drug candidates [27,28]. The introduction of fluorine atoms leads to a change in the solubility and lipophilicity of compounds, thus increasing their bioavailability and their cell membranes permeability.…”

3,4-Dideoxy-3,3,4,4-tetrafluoro- and 4-OH epimeric 3-deoxy-3,3-difluoro-α-GalCer analogues: Synthesis and biological evaluation on human iNKT cells stimulation

“…[118-8 122] While the blocking of metabolic sites is often achieved by fluorination, the strong fluorine 9 electronegativity induces modification of a range of relevant properties, such as pKa and hydrogen bond properties of adjacent functional groups, molecular conformation, and lipophilicity. [123][124][125][126][127][128][129][130][131][132] Tetrafluoroethylene (CF2-CF2) groups have received less attention as functional biological effectors, [133][134][135][136][137] relatively to -F and -CF3 groups. CF2 group has been shown to generate a widening of the C-CF2-C angle (~111-118°) and a narrowing of the F-C-F angle (~100-104°) relative to tetrahedral geometry.…”