title: Intestinally-targeted TGR5 agonists equipped with quaternary ammonium have an improved hypoglycemic effect and reduced gallbladder filling effect.
abstract: TGR5 activation of enteroendocrine cells increases glucagon-like peptide 1 (GLP-1) release, which maintains glycemic homeostasis. However, TGR5 activation in the gallbladder and heart is associated with severe side effects. Therefore, intestinally-targeted TGR5 agonists were suggested as potential hypoglycemic agents with minimal side effects. However, until now no such compounds with robust glucose-lowering effects were reported, especially in diabetic animal models. Herein, we identify a TGR5 agonist, 26a, which was proven to be intestinally-targeted through pharmacokinetic studies. 26a was used as a tool drug to verify the intestinally-targeted strategy. 26a displayed a robust and long-lasting hypoglycemic effect in ob/ob mice (once a day dosing (QD) and 18-day treatment) owing to sustained stimulation of GLP-1 secretion, which suggested that robust hypoglycemic effect could be achieved with activation of TGR5 in intestine alone. However, the gallbladder filling effect of 26a was rather complicated. Although the gallbladder filling effect of 26a was decreased in mice after once a day dosing, this side effect was still not eliminated. To solve the problem above, several research strategies were raised for further optimization.
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Cao
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China.|College of pharmacy, Nanchang University, Nanchang 330006, China.
authors.forename: Zhi-Xiang
authors.initials: ZX
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Meng-Meng
authors.initials: MM
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: Qing-An
authors.initials: QA
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: 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: Yang-Liang
authors.initials: YL
authors.lastname: Ye
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.
authors.forename: Jian-Hua
authors.initials: JH
authors.lastname: Shen
mesh_terms: D064751:Ammonium Compounds / Q000494:pharmacology; D000818:Animals; D001786:Blood Glucose; D004195:Disease Models, Animal; D019858:Enteroendocrine Cells / Q000187:drug effects; D005260:Female; D005704:Gallbladder / Q000378:metabolism*; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D005951:Glucose Tolerance Test; D057809:HEK293 Cells; D006706:Homeostasis; D006801:Humans; D007003:Hypoglycemia / Q000188:drug therapy* / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008820:Mice, Obese; D010539:Permeability; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology*; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*
chemical_list: D064751:Ammonium Compounds; D001786:Blood Glucose; C473772:GPBAR1 protein, human; C513561:Gpbar1 protein, mouse; D007004:Hypoglycemic Agents; D000644:Quaternary Ammonium Compounds; D043562:Receptors, G-Protein-Coupled; D052216:Glucagon-Like Peptide 1