4-Benzofuranyloxynicotinamide derivatives are novel potent and orally available TGR5 agonists

• 4-Benzofuranyloxynicotinamide derivatives were novel potent TGR5 agonists.
• The hTGR5 and mTGR5 EC50 for 9r was 0.28 nM and 0.92 nM, respectively.
• 19 displayed low permeability (Papp = 0.21 × 10−6 cm/s) and moderate potency.
• Both 9r and 19 could effectively lower the blood glucose in ICR mice.
• 19 still increased the gallbladder volume of mice.

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.

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