Optimization of compound lipophilicity is a key aspect of drug discovery. The aim of this work was to compare the lipophilicity modulations induced by 16 distinct known and novel fluoroalkyl motifs on three parent models. Fifty fluorinated compounds, with 28 novel experimental aliphatic logP values, are involved in discussing various lipophilicity trends. As well as confirming known trends, a number of novel lipophilicity reducing motifs are introduced. Tactics to reduce lipophilicity are discussed, such as "motif extensions" and "motif rearrangements", including with concomitant extension of the carbon chain, as well as one-

No abstract

Bioactive compounds generally need to cross membranes to arrive at their site of action. The octanol‐water partition coefficient (lipophilicity, logPOW) has proven to be an excellent proxy for membrane permeability. In modern drug discovery, logPOW and bioactivity are optimized simultaneously, for which fluorination is one of the relevant strategies. The question arises as to which extent the often subtle logP modifications resulting from different aliphatic fluorine‐motif introductions also lead to concomitant membrane permeability changes, given the difference in molecular environment between octanol and (anisotropic) membranes. It was found that for a given compound class, there is excellent correlation between logPOW values with the corresponding membrane molar partitioning coefficients (logKp); a study enabled by novel solid‐state 19F NMR MAS methodology using lipid vesicles. Our results show that the factors that cause modulation of octanol‐water partition coefficients similarly affect membrane permeability.

No abstract

Bioactive compounds generally need to cross membranes to arrive at their site of action. The octanol‐water partition coefficient (lipophilicity, logPOW) has proven to be an excellent proxy for membrane permeability. In modern drug discovery, logPOW and bioactivity are optimized simultaneously, for which fluorination is one of the relevant strategies. The question arises as to which extent the often subtle logP modifications resulting from different aliphatic fluorine‐motif introductions also lead to concomitant membrane permeability changes, given the difference in molecular environment between octanol and (anisotropic) membranes. It was found that for a given compound class, there is excellent correlation between logPOW values with the corresponding membrane molar partitioning coefficients (logKp); a study enabled by novel solid‐state 19F NMR MAS methodology using lipid vesicles. Our results show that the factors that cause modulation of octanol‐water partition coefficients similarly affect membrane permeability.