TGR5 Agonist Program

TGR5 is a member of the of the GPCR superfamily which is highly expressed in the gall bladder and intestine. Bile acids have been implicated as endogenous TGR5 agonists, and studies have shown an ability for them to increase secreation of glucagon-like-peptide-1 (GLP-1), a hormone that affects multiple metabolic parameters including insulin secretion from the pancreas and blood glucose levels. Stimulating GLP-1 secretion by activation of TGR5 is a therapeutic approach to the use of DPP-IV inhibitors for the treatment of diabetes. Exelixis discovered a series of orally administered TGR5 agonists including XL475, which advanced to development compound status internally. XL475 and related compounds increase GLP-1 secretion and may improve insulin sensitivity in multiple species.

The program was outlicensed to Bristol Myers Squibb in October 2010. Characterization of XL475 and related compounds in preclinical models is ongoing at BMS.