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.
Highlights
TGR5 activation in other tissues can cause some side effects, of which those in the gallbladder and heart are the main concerns
Quaternary ammonium was incorporated to 9a to yield a series of TGR5 agonists, among which 26a displayed the best activity in vitro and extremely low Caco-2 cell permeability (Papp = 0.06 × 10−6 cm/s). 26a could be classified as a low-permeability agent
26a exhibited a consistent hypoglycemic effect throughout the 18-day treatment of ob/ob mice. These data confirmed that a robust hypoglycemic effect could be achieved by intestinal activation of TGR5 independent of systemic exposure
Summary
TGR5 activation in other tissues can cause some side effects, of which those in the gallbladder and heart are the main concerns. To investigate whether 26a with a low-permeability profile could display a robust hypoglycemic effect and a reduced gallbladder filling effect, once a day oral dosing (QD) and long-term effect of 26a in animal models were determined. After once a day oral dose of 2 (50 mg/kg) to ICR mice, gallbladder area and bile weight increased 143% and 108%, respectively, compared with the control group.
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