Design of Gut-Restricted Thiazolidine Agonists of G Protein-Coupled Bile Acid Receptor 1 (GPBAR1, TGR5)

Bile
acid signaling and metabolism in the gastrointestinal tract
have wide-ranging influences on systemic disease. G protein-coupled
bile acid receptor 1 (GPBAR1, TGR5) is one of the major effectors
in bile acid sensing, with demonstrated influence on metabolic, inflammatory,
and proliferative processes. The pharmacologic utility of TGR5 agonists
has been limited by systemic target-related effects such as excessive
gallbladder filling and blockade of gallbladder emptying. Gut-restricted
TGR5 agonists, however, have the potential to avoid these side effects
and consequently be developed into drugs with acceptable safety profiles.
We describe the discovery and optimization of a series of gut-restricted
TGR5 agonists that elicit a potent response in mice, with minimal
gallbladder-related effects. The series includes 12 (TGR5
EC50: human, 143 nM; mouse, 1.2 nM), a compound with minimal
systemic availability that may have therapeutic value to patients
with type 2 diabetes mellitus, nonalcoholic steatohepatitis, or inflammatory
bowel disease.