Chronic Exposure to SCO-267, an Allosteric GPR40 Full Agonist, Is Effective in Improving Glycemic Control in Rats

Abstract

Full agonist-mediated activation of free fatty acid receptor 1 (FFAR1/GPR40) alleviates diabetes in rodents. Considering that diabetes is a chronic disease, assessment of treatment durability of chronic exposure to a GPR40 full agonist is pivotal for treating patients with diabetes. However, the physiological significance of chronic in vitro and in vivo exposure to GPR40 full agonists is largely unclear. Here, we evaluated the in vitro and in vivo effects of chronic treatment with SCO-267, a GPR40 full agonist, on signal transduction and glucose control. In vitro experiments showed that SCO-267 is an allosteric full agonist for GPR40, which activates the Gα q , Gα s , and Gα 12/13 pathways and β-arrestin recruitment. The calcium signal response was largely sustained in GPR40-overexpressing CHO cells even after prolonged incubation with SCO-267. To evaluate the in vivo relevance of chronic exposure to GPR40 full agonists, SCO-267 (1 and 10 mg/kg) was administered once daily to neonatally streptozotocin-induced diabetic rats for 15-33 days, and glucose control was evaluated. After 15 days of dosing followed by the drug wash-out period, SCO-267 improved glucose tolerance most likely by increasing insulin sensitivity in rats. After 33 days, repeated exposure to SCO-267 was highly effective in improving glucose tolerance in rats. Furthermore, chronic exposure to SCO-267 increased pancreatic insulin content. These results demonstrated that even after chronic exposure, SCO-267 effectively activates GPR40 in cells and rats, suggesting the clinical application of SCO-267 in treating chronic diseases This article has not been copyedited and formatted. The final version may differ from this version.

SCO-267, a GPR40 Full Agonist, Stimulates Islet and Gut Hormone Secretion and Improves Glycemic Control in Humans

“…Furthermore, multiple doses of SCO-267 were able to repeatedly simulate the secretion of insulin, glucagon, GLP-1, GIP, and PYY. A preclinical study demonstrated that chronic 24-h exposure to SCO-267 for 5 weeks was highly effective in improving glucose tolerance in diabetic rats (19). Overall, these results suggest that repeated once-daily oral administration of SCO-267 is likely to improve glycemic control in patients with diabetes, and its use should be evaluated for longer periods in clinical trials.…”

“…SCO-267 at a dose of 0.3 mg/kg exhibited a C max value of 22.7 ng/mL and was more effective at improving glucose control than the clinically translatable doses of sitagliptin, a dipeptidyl peptidase 4 inhibitor, and fasiglifam in diabetic rats (16,17). In addition, a preclinical study demonstrated that chronic 24-h exposure to SCO-267 was highly effective in improving glycemic control in diabetic rats (19). Therefore, oncedaily dosing of $10 mg SCO-267 might be sufficient to improve glycemic control for 24 h in clinical settings.…”

Preclinical pharmacokinetics and metabolism study of SCO‐267, a GPR40 full agonist, in beagle dogs using ultra‐high performance liquid chromatography coupled to tandem mass spectrometry

“…SCO‐267 can decrease liver triglyceride content and plasma alanine aminotransferase amount without affecting food intake and body weight in NAFLD mouse (Ookawara et al, 2020). It has been demonstrated that SCO‐267 improved glucose tolerance in rats after 15 days of dosing and chronic exposure to SCO‐267 increased pancreatic insulin levels (Koyama et al, 2021). Clinical experiments indicated that SCO‐267 was safe and well tolerated (Nishizaki et al, 2021).…”