Synthesis of 12β-methyl-18-nor-avicholic acid analogues as potential TGR5 agonists. Issue 17 (1st March 2022)

• Record Type: Journal Article
• Authors: Ure, Elizabeth M.; Harris, Lawrence D.; Cameron, Scott A.; Weymouth-Wilson, Alex; Furneaux, Richard H.; Pitman, Janet L.; Hinkley, Simon. F.; Luxenburger, Andreas
• Is Part Of: Organic & biomolecular chemistry. Volume 20:Issue 17(2022)
• Page Start: 3511
• Page End: 3527
• Publication Date: 2022-03-01
• Subjects: Chemistry, Organic -- Periodicals; Bioorganic chemistry -- Periodicals; Chemistry, Physical organic -- Periodicals; 547
• DOI: 10.1039/d1ob02401a
• Languages: English
• ISSNs: 1477-0520

Abstract

Abstract : A series of 12β-methyl-18- nor -avicholic acid analogues was prepared and evaluated for activity at TGR5 and FXR. Compounds 46 and 53 emerged as low-micromolar TGR5 agonists, providing potential new templates for further development. Abstract : 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 13(17) -12β-methyl-18- nor -chenodeoxycholic acid intermediate (16 ), the synthesis of which we reported previously. The preparation of these aptly named 12β-methyl-18- nor -avicholic acids (17, 18, 41 and 42 ) 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 (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 R )-12β, 23-dimethyl-18- nor -chenodeoxycholic acid (46 ) and 12β-methyl-17- epi -18- nor -chenodeoxycholic acid 53 as TGR5 ligands with EC50 values of 25 μM.