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The University of Southampton
Chemistry

Research project: Linclau: The Influence of Fluorination on Lipophilicity

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Lipophilicity (logP) is linked to the capacity of compounds to pass cell membranes, and defined as the partition coefficient P between octanol and water. It is one of the most important ADMET parameters, and features in the Lipinski rule of 5.

 

In drug development, the optimisation for potency is a natural focus However, potency gain achieved at the expense of physicochemical and pharmacokinetic properties is compromising drug efficacy and safety, increasing the chance of attrition. In this regard, the inappropriate use of lipophilicity to build potency, described as “Molecular Obesity“, has been identified as a key problem. Given late stage drug attrition is a very costly affair, and a key contemporary problem in the pharmaceutical industry, research that provides insights in how lipophilicity can be controlled is timely and of great interest. Since fluorine is introduced in drug development programmes for the optimisation/introduction of an ever-increasing list of properties, it is important to better understand how the fluorination used for that purpose has an impact on the lipophilicity. Or, perhaps more importantly, to investigate how direct lipophilicity modulation by fluorination can be achieved using a broader arsenal of possible motifs than currently available.

Research into the relationship between logP and structure is thus of very high importance, and it is well established that lipophilicity is influenced by fluorination. While aromatic fluorination is well-understood (and increases logP), the systematic study of the relationship(s) between aliphatic fluorination and lipophilicity has only just started, and is complicated by a balance of two competing effects: hydrophilicity is favoured by the increase in polarity due to the strong C–F dipole moment, but disfavoured by the increase in hydrophobic surface area. The relationship is further influenced by structural rigidity, proximity of the fluorination with functional groups, the actual logP of the parent substrate, etc. Hence aliphatic fluorine introduction frequently decreases logP, which is still not widely appreciated.

Our group has developed a new, practical “shake flask”-based method to determine the octanol-water partition coefficient POW (hereafter called P) of non-UV active fluorinated compounds X (Angew Chem 2016, 55, 674 (VIP)). It is based on the use of an internal reference ref, allowing the measurement of a ratio p (eq. 1, Fig 1) of 19F NMR peak integratals of X and ref in each phase, which equates to their ratio of the respective P values from which eq 4 can be derived. Our results indicate that this straightforward method allows for the accurate determination of lipophilicity (±0.01 logP unit, currently ~logP ±3).

 

 

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Our first set of data for conformationally flexible and rigid fluorohydrins already provided a wealth of information, including the identification of polyfluorinated motifs that lower the logP. We also obtained the first lipophilicity values of fluorinated carbohydrates. Further refinements of the methodology are in development, and we are investigating a wider range of fluorinated motifs, and compound classes. This work is currently sponsored by AstraZeneca.

Related research groups

Organic Chemistry: Synthesis, Catalysis and Flow
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