PT  - JOURNAL ARTICLE
AU  - Hikaru Ueno
AU  - Ryo Ito
AU  - Shin-ichi Abe
AU  - Mitsugi Ookawara
AU  - Hirohisa Miyashita
AU  - Hitomi Ogino
AU  - Yasufumi Miyamoto
AU  - Tomoki Yoshihara
AU  - Akihiro Kobayashi
AU  - Yoshiyuki Tsujihata
AU  - Koji Takeuchi
AU  - Masanori Watanabe
AU  - Yukio Yamada
AU  - Tsuyoshi Maekawa
AU  - Nobuhiro Nishigaki
AU  - Yusuke Moritoh
TI  - SCO-267, a GPR40 Full Agonist, Improves Glycemic and Body Weight Control in Rat Models of Diabetes and Obesity
AID  - 10.1124/jpet.118.255885
DP  - 2019 Aug 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 172--181
VI  - 370
IP  - 2
4099  - http://jpet.aspetjournals.org/content/370/2/172.short
4100  - http://jpet.aspetjournals.org/content/370/2/172.full
SO  - J Pharmacol Exp Ther2019 Aug 01; 370
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.