Synthesis of Novel C/D Ring Modified Bile Acids

Bile acid receptors have been identified as important targets for the development of new therapeutics to treat various metabolic and inflammatory diseases. The synthesis of new bile acid analogues can help elucidate structure–activity relationships and define compounds that activate these receptors selectively. Towards this, access to large quantities of a chenodeoxycholic acid derivative bearing a C-12 methyl and a C-13 to C-14 double bond provided an interesting scaffold to investigate the chemical manipulation of the C/D ring junction in bile acids. The reactivity of this alkene substrate with various zinc carbenoid species showed that those generated using the Furukawa methodology achieved selective α-cyclopropanation, whereas those generated using the Shi methodology reacted in an unexpected manner giving rise to a rearranged skeleton whereby the C ring has undergone contraction to form a novel spiro–furan ring system. Further derivatization of the cyclopropanated steroid included O-7 oxidation and epimerization to afford new bile acid derivatives for biological evaluation

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 Δ13(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 (23R)-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

The discovery of 12β-methyl-17-epi-18-nor-bile acids as potent and selective TGR5 agonists

Recent discoveries have demonstrated that the physiological function of bile acids extends to the regulation of diverse signaling processes through interactions with nuclear and G protein-coupled receptors, most notably the Farnesoid-X nuclear receptor (FXR) and the G protein-coupled bile acid receptor 1 (GPBAR1, also known as TGR5). Targeting such signaling pathways pharmacologically, i.e. with bile acid-derived therapeutics, presents great potential for the treatment of various metabolic, inflammatory immune, liver, and neurodegenerative diseases. Here we report the discovery of two potent and selective TGR5 agonists (NZP196 and 917). These compounds are the taurine conjugates of 6α-ethyl-substituted 12β-methyl-18-nor-bile acids with the side chain being located on the α-face of the steroid scaffold. The compounds emerged from a screening effort of a diverse library of 12β-methyl-18-nor-bile acids that were synthesized from 12β-methyl-18-nor-chenodeoxycholic acid and its C17-epimer. Upon testing for FXR activity, both compounds were found to be inactive, thus revealing selectivity for TGR5

IMINORIBITOL-MODIFIED 3,4-DIARYL-ISOXAZOLES AS POTENT INHIBITORS OF CK1δ/ε

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The Discovery of 12β-Methyl-18-nor-Bile Acids as Potent and Selective TGR5 Agonists

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