Structure-guided discovery of cholic acid derivatives as potent and selective TGR5 allosteric agonists for the treatment of diabetes

In this work, we designed and synthesized 48 new cholic acid (CA) derivatives as potential Takeda G protein coupled receptor 5 (TGR5) positive allosteric modulators (PAMs). The GloSensor cyclic adenosine monophosphate (cAMP) accumulation assay was used to evaluate the potency and mechanism of action of target compounds. Pharmacological results showed that all final compounds were capable of activating the TGR5. Interestingly, compound B1, selective methylation of 7-hydroxyl group in CA, displayed 80-fold higher potency for TGR5 than its lead compound CA. Furthermore, B1 positively modulated the functionality and potency of lithocholic acid (LCA) in TGR5, indicative of positive allosteric effect. Notably, 12-ketone derivative A1 showed 65-fold higher activity for TGR5 compared with CA. Unexpectedly, compound A1 revealed the same positive allostery as B1, indicating that A1 is also a TGR5 PAM. Molecular docking study exhibited that 12-ketone in A1 and 12-hydroxyl group in B1 formed hydrogen bolds with the key amino acid Thr131, which play important roles in TGR5 allosteric function. More importantly, B1 displayed a significant glucose-lowering effect in the oral glucose tolerance test (OGTT) in mice. Overall, we discovered a potent and selective TGR5 allosteric agonist B1, which could be used as lead compound to further study TGR5 allostery with antidiabetic effect.

Allosteric mechanism; Antidiabetic effects; G protein coupled bile acid receptor 1; Structure-activity relationships; TGR5 allosteric agonists.