title: Discovery of 6alpha-ethyl-23(S)-methylcholic acid (S-EMCA, INT-777) as a potent and selective agonist for the TGR5 receptor, a novel target for diabesity.
abstract: In the framework of the design and development of TGR5 agonists, we reported that the introduction of a C(23)(S)-methyl group in the side chain of bile acids such as chenodeoxycholic acid (CDCA) and 6-ethylchenodeoxycholic acid (6-ECDCA, INT-747) affords selectivity for TGR5. Herein we report further lead optimization efforts that have led to the discovery of 6alpha-ethyl-23(S)-methylcholic acid (S-EMCA, INT-777) as a novel potent and selective TGR5 agonist with remarkable in vivo activity.
authors.affiliation: Dipartimento di Chimica e Tecnologia del Farmaco, Universita di Perugia, 06123 Perugia, Italy. rp@unipg.it
authors.forename: Roberto
authors.initials: R
authors.lastname: Pellicciari
authors.forename: Antimo
authors.initials: A
authors.lastname: Gioiello
authors.forename: Antonio
authors.initials: A
authors.lastname: Macchiarulo
authors.forename: Charles
authors.initials: C
authors.lastname: Thomas
authors.forename: Emiliano
authors.initials: E
authors.lastname: Rosatelli
authors.forename: Benedetto
authors.initials: B
authors.lastname: Natalini
authors.forename: Roccaldo
authors.initials: R
authors.lastname: Sardella
authors.forename: Mark
authors.initials: M
authors.lastname: Pruzanski
authors.forename: Aldo
authors.initials: A
authors.lastname: Roda
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Pastorini
authors.forename: Kristina
authors.initials: K
authors.lastname: Schoonjans
authors.forename: Johan
authors.initials: J
authors.lastname: Auwerx
mesh_terms: D000818:Animals; D016466:CHO Cells; D019556:COS Cells; D002522:Chlorocebus aethiops; D002793:Cholic Acids / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D006224:Cricetinae; D003412:Cricetulus; D003920:Diabetes Mellitus / Q000188:drug therapy; D006801:Humans; D009765:Obesity / Q000188:drug therapy; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000378:metabolism; D013237:Stereoisomerism
chemical_list: C545501:6alpha-ethyl-23(S)-methylcholic acid; D002793:Cholic Acids; C473772:GPBAR1 protein, human; D043562:Receptors, G-Protein-Coupled