The synthesis of fluorinated obeticholic acid derivatives

Abstract

Bile acids are steroids found naturally within the bile of humans and other vertebrates. Their physiological roles involve the solubilisation of dietary lipids, lipophilic vitamins and drugs and also the regulation of hepatic cholesterol levels. Additionally, in recent years, bile acids have been found to act as an agonist of receptors such as the FXR nuclear receptor and the TGR5 membrane-bound receptor. This has led to both natural and semi-synthetic bile acids being investigated as drug candidates for treatment of conditions including cancer, Parkinson’s disease, Alzheimer’s disease, diabetes, metabolic disorder and liver diseases. Of the semi-synthetic bile acids developed, obeticholic acid (OCA) has been observed to have a promising effect on the liver disease non-alcoholic steatohepatitis (NASH) and is progressing through clinical trials. Organically bound fluorine is seeing increasing use within drug discovery, with as many as 20% of the current drug molecules on the market containing at least one fluorine atom. Fluorine’s uses in this context include modification of physiochemical properties, such as hydrogen bond donating capacity, pKa and lipophilicity. As a result, synthesis of fluorinated bile acids as potential drug candidates is of particular interest. This thesis describes the synthesis of a number of fluorinated and non-fluorinated OCA analogues, as well as fluorinated OCA analogues with modification of the side chain carboxylic acid. Synthesised analogues were also tested for their biological activity, with the focus on treatment of NASH

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

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