title: Design, synthesis, and antidiabetic activity of 4-phenoxynicotinamide and 4-phenoxypyrimidine-5-carboxamide derivatives as potent and orally efficacious TGR5 agonists.
abstract: 4-Phenoxynicotinamide and 4-phenoxypyrimidine-5-carboxamide derivatives as potent and orally efficacious TGR5 agonists are reported. Several 4-phenoxynicotinamide derivatives were found to activate human and mouse TGR5 (hTGR5 and mTGR5) with EC50 values in the low nanomolar range. Compound 23g, with an EC50 value of 0.72 nM on hTGR5 and an EC50 value of 6.2 nM on mTGR5, was selected for further in vivo efficacy studies. This compound exhibited a significant dose-dependent glucagon-like peptide-1 (GLP-1) secretion effect. A single oral dose of 23g (50 mg/kg) significantly reduced blood glucose levels in db/db mice and caused a 49% reduction in the area under the blood glucose curve (AUC)0-120 min following an oral glucose tolerance test (OGTT) in imprinting control region (ICR) mice. However, 23g stimulated gallbladder filling, which might result in side effects to the gallbladder.
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Hongliang
authors.initials: H
authors.lastname: Duan
authors.forename: Mengmeng
authors.initials: M
authors.lastname: Ning
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Chen
authors.forename: Qingan
authors.initials: Q
authors.lastname: Zou
authors.forename: Liming
authors.initials: L
authors.lastname: Zhang
authors.forename: Ying
authors.initials: Y
authors.lastname: Feng
authors.forename: Lina
authors.initials: L
authors.lastname: Zhang
authors.forename: Ying
authors.initials: Y
authors.lastname: Leng
authors.forename: Jianhua
authors.initials: J
authors.lastname: Shen
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D005951:Glucose Tolerance Test; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: C578440:4-phenoxynicotinamide; C578441:4-phenoxypyrimidine-5-carboxamide; D001786:Blood Glucose; C473772:GPBAR1 protein, human; C513561:Gpbar1 protein, mouse; D007004:Hypoglycemic Agents; D011743:Pyrimidines; D043562:Receptors, G-Protein-Coupled; D009536:Niacinamide