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- W4365516418 abstract "<p>Bile acids are amphiphilic steroids which serve to emulsify lipophilic nutrients and assist with the elimination of harmful substances from the body. Since the turn of the century, it has become apparent that bile acids have a secondary function as endocrine and paracrine signalling molecules, allowing them to mediate cholesterol, lipid and glucose homeostasis. This is achieved through interactions with nuclear and membrane-bound receptors such as the Farensoid X receptor (FXRα) and the G protein-coupled bile acid receptor (TGR5). These receptors are involved in the pathogenesis of metabolic and inflammatory liver disorders including: diabetes, obesity, non-alcoholic steatohepatitis and primary biliary cholangitis. Therefore, the bile acid-activated receptors have become attractive therapeutic targets.</p> <p><br></p> <p>The research herein describes the synthesis of bile acid scafolds in the search for candidates with high pharmacological activity at TGR5 and FXRα. The synthetic strategy began with a scalable Wanger-Meerwein type rearrangement of cholic acid, resulting in the preparation of novel chenodeoxycholic isomers. Further chemical manipulation of these chenodeoxycholic acid derivatives, with a focus on oxidation and alkylation chemistry, facilitated the development of a range of natural product analogues. Such compounds were included in a biological screen against TGR5 and FXRα, allowing an investigation into the structural elements required to affect the bile acid-activated receptors. This led to the identification of new agonists for TGR5; compounds with a pharmacodynamic response that rivals the leading TGR5 drug candidates currently in pre-clinical-development.</p>" @default.
- W4365516418 created "2023-04-15" @default.
- W4365516418 creator A5062606326 @default.
- W4365516418 date "2023-04-14" @default.
- W4365516418 modified "2023-10-01" @default.
- W4365516418 title "Targeted Synthesis of Novel Bile Acids" @default.
- W4365516418 doi "https://doi.org/10.26686/wgtn.22631365" @default.
- W4365516418 hasPublicationYear "2023" @default.
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