title: Structure-activity relationship study of betulinic acid, a novel and selective TGR5 agonist, and its synthetic derivatives: potential impact in diabetes.
abstract: We describe here the biological screening of a collection of natural occurring triterpenoids against the 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), and ursolic acid (3) exhibited TGR5 agonist activity in a selective manner compared to bile acids, which also activated FXR, the nuclear bile acid receptor. The most potent natural triterpenoid betulinic acid was chosen as a reference compound for an SAR study. Hemisyntheses were performed on the betulinic acid scaffold, and we focused on structural modifications of the C-3 alcohol, the C-17 carboxylic acid, and the C-20 alkene. In particular, structural variations around the C-3 position gave rise to major improvements of potency exemplified with derivatives 18 dia 2 (RG-239) and 19 dia 2. The best derivative was tested in vitro and in vivo, and its biological profile is discussed.
authors.affiliation: UMR/CNRS 7199, Faculte de pharmacie, Universite Louis Pasteur, 67404 Illkirch, France.
authors.forename: Cédric
authors.initials: C
authors.lastname: Genet
authors.forename: Axelle
authors.initials: A
authors.lastname: Strehle
authors.forename: Céline
authors.initials: C
authors.lastname: Schmidt
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Boudjelal
authors.forename: Annelise
authors.initials: A
authors.lastname: Lobstein
authors.forename: Kristina
authors.initials: K
authors.lastname: Schoonjans
authors.forename: Michel
authors.initials: M
authors.lastname: Souchet
authors.forename: Johan
authors.initials: J
authors.lastname: Auwerx
authors.forename: Régis
authors.initials: R
authors.lastname: Saladin
authors.forename: Alain
authors.initials: A
authors.lastname: Wagner
mesh_terms: D041721:3T3-L1 Cells; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008968:Molecular Conformation; D053978:Pentacyclic Triterpenes; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014315:Triterpenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000094062:Betulinic Acid
chemical_list: C473772:GPBAR1 protein, human; D053978:Pentacyclic Triterpenes; D043562:Receptors, G-Protein-Coupled; D014315:Triterpenes; D000094062:Betulinic Acid