title: 4-Benzofuranyloxynicotinamide derivatives are novel potent and orally available TGR5 agonists.
abstract: A series of 4-benzofuranyloxynicotinamide derivatives were identified to be novel, potent, and orally available TGR5 agonists. Among them, compound 9r had the highest potency in vitro (hTGR5 EC50 = 0.28 nM, mTGR5 EC50 = 0.92 nM). Further in vivo studies disclosed that 9r could effectively lower the blood glucose, but meantime caused an increase in the gallbladder volume of mice. Subsequent research toward eliminating the gallbladder toxicity resulted in compound 19 with low permeability. Although the EC50 of mTGR5 of 19 was larger one order than that of 9r, it still had good glucose-lowing activity. Nevertheless, 19 also caused the adverse effects to the gallbladder. The drug levels detection disclosed that the concentration of 19 was only lower than that of 9r in plasma but was higher in bile and gallbladder tissue. This result indicated that low exposure in plasma could not guarantee low exposure in bile and gallbladder tissue, and thus resulting in the gallbladder toxicity of 19.
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Qingan
authors.initials: Q
authors.lastname: Zou
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.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Mengmeng
authors.initials: M
authors.lastname: Ning
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Feng
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Liming
authors.initials: L
authors.lastname: Zhang
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.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Leng
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: jhshen@mail.shcnc.ac.cn.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Shen
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001572:Benzofurans / Q000737:chemistry / Q000494:pharmacology*; D018938:Caco-2 Cells; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D015394:Molecular Structure; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: D001572:Benzofurans; C473772:GPBAR1 protein, human; C513561:Gpbar1 protein, mouse; D043562:Receptors, G-Protein-Coupled; D009536:Niacinamide
keywords: 4-Benzofuranyloxynicotinamide; Caco-2 permeability; Gallbladder toxicity; TGR5