RT Journal Article SR Electronic T1 SCO-267, a GPR40 Full Agonist, Improves Glycemic and Body Weight Control in Rat Models of Diabetes and Obesity JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 172 OP 181 DO 10.1124/jpet.118.255885 VO 370 IS 2 A1 Ueno, Hikaru A1 Ito, Ryo A1 Abe, Shin-ichi A1 Ookawara, Mitsugi A1 Miyashita, Hirohisa A1 Ogino, Hitomi A1 Miyamoto, Yasufumi A1 Yoshihara, Tomoki A1 Kobayashi, Akihiro A1 Tsujihata, Yoshiyuki A1 Takeuchi, Koji A1 Watanabe, Masanori A1 Yamada, Yukio A1 Maekawa, Tsuyoshi A1 Nishigaki, Nobuhiro A1 Moritoh, Yusuke YR 2019 UL http://jpet.aspetjournals.org/content/370/2/172.abstract AB The GPR40/FFA1 receptor is a G-protein-coupled receptor expressed in the pancreatic islets and enteroendocrine cells. Here, we report the pharmacological profiles of (3S)-3-cyclopropyl-3-{2-[(1-{2-[(2,2-dimethylpropyl)(6-methylpyridin-2-yl)carbamoyl]-5-methoxyphenyl}piperidin-4-yl)methoxy]pyridin-4-yl}propanoic acid (SCO-267), a novel full agonist of GPR40. Ca2+ signaling and insulin and glucagon-like peptide-1 (GLP-1) secretion were evaluated in GPR40-expressing CHO, MIN6, and GLUTag cells. Hormone secretions and effects on fasting glucose were tested in rats. Single or repeated dosing effects were evaluated in neonatally streptozotocin-induced diabetic rats (N-STZ-1.5 rats), diet-induced obese (DIO) rats, and GPR40-knockout (Ffar1–/–) mice. Treatment with SCO-267 activated Gq signaling in both high- and low-FFAR1–expressing CHO cells, stimulated insulin secretion in MIN6 cells, and induced GLP-1 release in GLUTag cells. When administered to normal rats, SCO-267 increased insulin, glucagon, GLP-1, glucose-dependent insulinotropic peptide, and peptide YY (PYY) secretions under nonfasting conditions. These results show the full agonistic property of SCO-267 against GPR40. Hypoglycemia was not induced in SCO-267–treated rats during the fasting condition. In diabetic N-STZ-1.5 rats, SCO-267 was highly effective in improving glucose tolerance in single and 2-week dosing studies. DIO rats treated with SCO-267 for 2 weeks showed elevated plasma GLP-1 and PYY levels, reduced food intake, and decreased body weight. In wild-type mice, SCO-267 induced GLP-1 secretion, food intake inhibition, and body weight reduction; however, these effects were abolished in Ffar1–/– mice, indicating a GPR40-dependent mechanism. In conclusion, SCO-267 stimulated islet and gut hormone secretion, improved glycemic control in diabetic rats, and decreased body weight in obese rats. These data suggest the therapeutic potential of SCO-267 for the treatment of diabetes and obesity.