Structure-activity relationship study of betulinic acid, a novel and selective TGR5 agonist, and its synthetic derivatives: potential impact in diabetes.

摘要: We describe here the biological screening of a collection natural occurring triterpenoids against G protein-coupled receptor TGR5, known to be activated by bile acids and which mediates some important cell functions. This work revealed that betulinic (1), oleanolic (2), ursolic acid (3) exhibited TGR5 agonist activity in selective manner compared acids, also FXR, nuclear receptor. The most potent triterpenoid was chosen as reference compound for an SAR study. Hemisyntheses were performed on scaffold, we focused structural modifications C-3 alcohol, C-17 carboxylic acid, C-20 alkene. In particular, variations around position gave rise major improvements potency exemplified with derivatives 18 dia 2 (RG-239) 19 2. best derivative tested vitro vivo, its profile is discussed.