March 2, 2022

Second research publication in collaboration with ICE Pharma and Ferrier Research Institute

Synthesis of 12β-methyl-18-nor-avicholic acid analogues as potential TGR5 agonists

In the quest for new modulators of the Farnesoid-X (FXR) and Takeda G-protein-coupled (TGR5) receptors, bile acids are a popular candidate for drug development. Recently, bile acids endowed with a C16-hydroxy group emerged as ligands of FXR and TGR5 with remarkable agonistic efficacies. Inspired by these findings, we synthesised a series of C16-hydroxylated 12β-methyl-18-nor-bile acid analogues from a Δ-12β-methyl-18-nor-chenodeoxycholic acid intermediate, the synthesis of which we reported previously. The preparation of these aptly named 12β-methyl-18-nor-avicholic acids was accomplished via allylic oxidation at C16, hydrogenation of the C13→C17 double bond and selective reduction of the C16-carbonyl group. Described also are various side products which were isolated during the evaluation of methods to affect the initial allylic oxidation. In addition, C23-methyl modified 12β-methyl-18-nor-bile acids with and without a C16-hydroxy group, were synthesized to enable comparison of biological activities between these compounds and their un-methylated counterparts. As a result of our investigations we identified (23R)-12β,23-dimethyl-18-nor-chenodeoxycholic acid and 12β-methyl-17-epi-18-nor-chenodeoxycholic acid as TGR5 ligands with EC50 values of 25 μM.

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