The influence of aliphatic fluorination on lipophilicity

Abstract

Lipophilicity is known to influence a wide range of ADMET (absorption, distribution, metabolism, excretion and toxicity) properties and is widely regarded as one of the most important parameters within drug discovery programs. Unfortunately, in recent years lipophilicity modulation has often been abused to increase the potency of drug molecules. This has caused in an overall increase in lipophilicity for orally available drugs, typically resulting in undesirable effects on the aforementioned ADMET properties. Hence, as late-stage drug attrition is very costly, in order to improve the druggability of a compound there has been an increased awareness of the importance of lipophilicity modulation within drug discovery programs.

Fluorination is a tool commonly used within drug development to modulate a wide range of pharmacokinetic properties, in particular lipophilicity. While the effects of aromatic fluorination on lipophilicity have been well studied, due to constraints of commonly utilized analytical techniques used to measure lipophilicity (requirement of a UV chromophore), aliphatic fluorination has not. Fortunately, through the use of a 19F NMR based method, the effects of aliphatic fluorination can now be reliably measured. Therefore, within this thesis the synthesis and lipophilicity measurement of a wide range of fluorinated alkanols, containing both known and novel motifs, will be covered. This allowed for an in-depth discussion into the effects of aliphatic fluorination on lipophilicity. It is also of interest for medicinal chemists whether these lipophilicity modulations persist on more complex drug scaffolds. Hence, the incorporation of a series of interesting aliphatic fluorinated motifs into a drug molecule was performed and their influence on lipophilicity was reproduced.

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ORCID for Bruno Linclau: orcid.org/0000-0001-8762-0170

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