title: Design, synthesis and biological evaluation of a novel class of potent TGR5 agonists based on a 4-phenyl pyridine scaffold.
abstract: TGR5, a GPCR, is involved in energy and glucose homeostasis, and as such, is a target for the treatment of diabetes, obesity and other metabolic syndromes. A new class of TGR5 agonists based on a 4-phenyl pyridine scaffold was designed, synthesized and evaluated in vitro and in vivo. Extensive structure-activity relationship studies are reported herein. The most potent compounds 15a, 18b and 18c showed comparable activity with the lead compound 2. 15a had the best potency in vitro but displayed an unfavorable pharmacokinetic profile and was found to be ineffective during an oral glucose tolerance test in imprinting control region mice at a dose of 50 mg/kg.
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Junjie
authors.initials: J
authors.lastname: Zhu
authors.forename: Mengmeng
authors.initials: M
authors.lastname: Ning
authors.forename: Cen
authors.initials: C
authors.lastname: Guo
authors.forename: Lina
authors.initials: L
authors.lastname: Zhang
authors.forename: Guoyu
authors.initials: G
authors.lastname: Pan
authors.forename: Ying
authors.initials: Y
authors.lastname: Leng
authors.forename: Jianhua
authors.initials: J
authors.lastname: Shen
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D005947:Glucose / Q000008:administration & dosage; D005951:Glucose Tolerance Test; D006801:Humans; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D015394:Molecular Structure; D011725:Pyridines / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: C473772:GPBAR1 protein, human; D011725:Pyridines; D043562:Receptors, G-Protein-Coupled; C051448:4-phenylpyridine; D005947:Glucose
keywords: 4-Phenyl pyridine; Diabetes; GPCR; TGR5