The University of Southampton
University of Southampton Institutional Repository

The influence of aliphatic fluorination on lipophilicity

The influence of aliphatic fluorination on lipophilicity
The influence of aliphatic fluorination on lipophilicity
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.
University of Southampton
Jeffries, Benjamin, Francis Joseph
5dd25e94-d698-4270-9c65-800495794388
Jeffries, Benjamin, Francis Joseph
5dd25e94-d698-4270-9c65-800495794388
Linclau, Bruno
19b9cacd-b8e8-4c65-af36-6352cade84ba

Jeffries, Benjamin, Francis Joseph (2019) The influence of aliphatic fluorination on lipophilicity. University of Southampton, Doctoral Thesis, 305pp.

Record type: Thesis (Doctoral)

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.

Text
Benjamin Jeffries Thesis Final Version PDF - Version of Record
Restricted to Repository staff only until 30 June 2022.
Available under License University of Southampton Thesis Licence.

More information

Published date: February 2019

Identifiers

Local EPrints ID: 433177
URI: http://eprints.soton.ac.uk/id/eprint/433177
PURE UUID: b93d1891-48b3-451d-81c2-7cd2f3497130
ORCID for Bruno Linclau: ORCID iD orcid.org/0000-0001-8762-0170

Catalogue record

Date deposited: 09 Aug 2019 16:30
Last modified: 10 Aug 2019 00:37

Export record

Contributors

Author: Benjamin, Francis Joseph Jeffries
Thesis advisor: Bruno Linclau ORCID iD

University divisions

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×