TGR5 is a member of the rhodopsin-like superfamily of G-protein coupled receptors (Class A), which is activated by bile acids (BAs). Pharmacological targeting of TGR5 may be a promising strategy for the treatment of diabetes and associated metabolic disorders.Previously reported TGR5 agonists include natural products, such as steroidal ligands and triterpenoids, and synthetic small molecules. The most noteworthy compound is 6a-ethyl-23(S)-methyl cholic acid (S-EMCA, INT-777), which has shown good results in both EC50 (0.82 �M) and in vivo experiments, and is undergoing clinical trials.In an effort to discover more potent TGR5 agonists, we chose betulinic acid, the most potent natural triterpenoid, as a starting point for a SAR studies. Modifications were made to the betulinic acid scaffold, focusing on structural modifications of the C-3 alcohol, the C-17 carboxylic acid, and the C-20 alkene. Structural variations gave rise to major improvements in potency, yielding compounds more potent than INT-777. Our new approach to modifying betulinic acid, especially at the C-20 alkene, opens a broader space for derivatization of the triterpenoids and provides useful evidence for the design of the next generation of TGR5 agonists.

Structure-activity relationship study of betulinic acid as TGR5 agonist

247th National Meeting (2014)

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