GPR40/FFAR1 is a G-protein-coupled receptor expressed in pancreatic islets and enteroendocrine cells. SCO-267 is a novel full agonist of GPR40 being developed as a treatment for type 2 diabetes and obesity. The efficacy of SCO-267 was investigated in cells and animal models of diabetes and obesity. In animal studies, the efficacy of SCO-267 was compared with that of fasiglifam, a clinically effective GPR40 agonist. SCO-267 treatment activated Gq signaling in both high and low GPR40-expressing CHO cells, stimulated insulin secretion in MIN6 cells, and induced GLP-1 release in GLUTag cells. In rats, SCO-267 increased insulin, glucagon, GLP-1, GIP, and PYY secretion, without hypoglycemia. In the neonatal streptozotocin (N-STZ)-1.5 rat, a diabetic model with impaired beta-cell function, compared to fasiglifam, SCO-267 was more effective in stimulating insulin and GLP-1 secretion, and improving glucose tolerance. In a single dose study using N-STZ-1.5 rats, 0.3 mg/kg SCO-267 (Cmax 0.023 μg/mL) and 3 mg/kg fasiglifam (Cmax 6.2 μg/mL) exhibited similar glucose-lowering efficacies. In a two-week dosing study of N-STZ-1.5 rats, glucose tolerance was more effectively improved by 1 mg/kg SCO-267 (Cmax, 0.139 μg/mL; AUC0-24hr, 0.626 μg h/mL) than by 10 mg/kg fasiglifam (Cmax, 39.8 μg/mL; AUC0-24hr, 254.6 μg h/mL). Diet-induced obese rats treated with SCO-267 for 2 weeks showed elevated plasma GLP-1 and PYY, reduced food intake, and decreased body weight, whereas fasiglifam-treated rats were weight-neutral. The reduction in body weight by SCO-267 was abolished in GPR40 knockout mice. Plasma protein binding of SCO-267 was similar across species (99.6-99.7%), indicating that similar compound exposure may induce therapeutic effects in humans. SCO-267 showed good pharmacokinetic and safety profiles in preclinical studies. These results suggest that SCO-267 treatment may result in effective glycemic and body weight control in patients.

Disclosure

Y. Moritoh: Employee; Self; SCOHIA PHARMA, Inc. H. Ueno: Employee; Self; Takeda Pharmaceutical Company Limited. R. Ito: Employee; Self; Takeda Pharmaceutical Company Limited. S. Abe: Employee; Self; SCOHIA PHARMA, Inc. H. Miyashita: Employee; Self; Takeda Pharmaceutical Company Limited. H. Ogino: Employee; Self; Takeda Pharmaceutical Company Limited. M. Ookawara: Employee; Self; SCOHIA PHARMA, Inc. Y. Ishimura: Employee; Self; Takeda Pharmaceutical Company Limited. Y. Miyamoto: None. T. Yoshihara: Employee; Self; Takeda Pharmaceutical Company Limited. Employee; Spouse/Partner; Takeda Pharmaceutical Company Limited. Y. Tsujihata: Employee; Self; Takeda Pharmaceutical Company Limited. K. Takeuchi: Employee; Self; Takeda Pharmaceutical Company Limited. N. Nishigaki: Employee; Self; Takeda Pharmaceutical Company Limited. Y. Yamada: Board Member; Self; SCOHIA PHARMA, Inc. M. Watanabe: Employee; Self; SCOHIA PHARMA, Inc.

Funding

Takeda Pharmaceutical Company Limited; SCOHIA PHARMA, Inc.

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.