Synthesis of 12β-methyl-18--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--bile acid analogues from a Δ-12β-methyl-18--chenodeoxycholic acid intermediate (16), the synthesis of which we reported previously. The preparation of these aptly named 12β-methyl-18--avicholic acids (17, 18, 41 and 42) was accomplished 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--bile acids with (48, 49, 51 and 52) and without a C16-hydroxy group (45, 46 and 55), were synthesized to enable comparison of biological activities between these compounds and their un-methylated counterparts. As a result of our investigations we identified (23)-12β,23-dimethyl-18--chenodeoxycholic acid (46) and 12β-methyl-17--18--chenodeoxycholic acid 53 as TGR5 ligands with EC values of 25 μM.