Discovery of a structurally novel, potent, and once-weekly free fatty acid receptor 1 agonist for the treatment of diabetes.

Type 2 diabetes mellitus (T2DM) is a lifelong disease that requires long-term medication to control glucose levels, and thereby long-acting drug has been clinically needed for improving medical adherence. The free fatty acid receptor 1 (FFA1) was considered as a promising target for several diseases, such as T2DM, pain and fatty liver. However, no once-weekly FFA1 agonist has been reported until now. Herein, we report the successful discovery of ZLY50, the first once-weekly FFA1 agonist with a completely new chemotype, highly agonistic activity and selectivity on FFA1. Moreover, ZLY50 has enough brain exposure to activate FFA1 in brain, and it is the first orally available FFA1 agonist with analgesic activity. Notably, the long-term anti-diabetic and anti-fatty liver effects of ZLY50 (once-weekly) were better than those of HWL-088 (once-daily), a highly potent FFA1 agonist with far stronger glucose-lowering effect than Phase 3 clinical candidate TAK-875. Further mechanism studies suggested that ZLY50 alleviates fatty liver by regulating the expressions of genes related to lipid metabolism, mitochondrial function, and oxidative stress in liver.