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Research ArticleEndocrine and Diabetes

SCO-267, a GPR40 full agonist, improves glycemic and body weight control in rat models of diabetes and obesity

Hikaru Ueno, Ryo Ito, Shin-Ichi Abe, Mitsugi Ookawara, Hirohisa Miyashita, Hitomi Ogino, Yasufumi Miyamoto, Tomoki Yoshihara, Akihiro Kobayashi, Yoshiyuki Tsujihata, Koji Takeuchi, Masanori Watanabe, Yukio Yamada, Tsuyoshi Maekawa, Nobuhiro Nishigaki and Yusuke Moritoh
Journal of Pharmacology and Experimental Therapeutics June 11, 2019, jpet.118.255885; DOI: https://doi.org/10.1124/jpet.118.255885
Hikaru Ueno
1 Takeda Pharmaceutical Company Limited;
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Ryo Ito
1 Takeda Pharmaceutical Company Limited;
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Shin-Ichi Abe
2 SCOHIA PHARMA Inc.
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Mitsugi Ookawara
2 SCOHIA PHARMA Inc.
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Hirohisa Miyashita
1 Takeda Pharmaceutical Company Limited;
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Hitomi Ogino
1 Takeda Pharmaceutical Company Limited;
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Yasufumi Miyamoto
1 Takeda Pharmaceutical Company Limited;
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Tomoki Yoshihara
1 Takeda Pharmaceutical Company Limited;
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Akihiro Kobayashi
2 SCOHIA PHARMA Inc.
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Yoshiyuki Tsujihata
1 Takeda Pharmaceutical Company Limited;
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Koji Takeuchi
1 Takeda Pharmaceutical Company Limited;
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Masanori Watanabe
2 SCOHIA PHARMA Inc.
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Yukio Yamada
2 SCOHIA PHARMA Inc.
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Tsuyoshi Maekawa
2 SCOHIA PHARMA Inc.
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Nobuhiro Nishigaki
1 Takeda Pharmaceutical Company Limited;
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Yusuke Moritoh
2 SCOHIA PHARMA Inc.
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Abstract

GPR40/FFA1 receptor is a G-protein-coupled receptor expressed in the pancreatic islets and enteroendocrine cells. Here, we report the pharmacological profiles of 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 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 non-fasting 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.

  • diabetes
  • drug discovery
  • free fatty acid receptors
  • g protein-coupled receptors (GPCRS)
  • insulin
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 384 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 384, Issue 2
1 Feb 2023
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Research ArticleEndocrine and Diabetes

SCO-267, a GPR40 full agonist, improves glycemic and body weight control in rat models of diabetes and obesity

Hikaru Ueno, Ryo Ito, Shin-Ichi Abe, Mitsugi Ookawara, Hirohisa Miyashita, Hitomi Ogino, Yasufumi Miyamoto, Tomoki Yoshihara, Akihiro Kobayashi, Yoshiyuki Tsujihata, Koji Takeuchi, Masanori Watanabe, Yukio Yamada, Tsuyoshi Maekawa, Nobuhiro Nishigaki and Yusuke Moritoh
Journal of Pharmacology and Experimental Therapeutics June 11, 2019, jpet.118.255885; DOI: https://doi.org/10.1124/jpet.118.255885

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Research ArticleEndocrine and Diabetes

SCO-267, a GPR40 full agonist, improves glycemic and body weight control in rat models of diabetes and obesity

Hikaru Ueno, Ryo Ito, Shin-Ichi Abe, Mitsugi Ookawara, Hirohisa Miyashita, Hitomi Ogino, Yasufumi Miyamoto, Tomoki Yoshihara, Akihiro Kobayashi, Yoshiyuki Tsujihata, Koji Takeuchi, Masanori Watanabe, Yukio Yamada, Tsuyoshi Maekawa, Nobuhiro Nishigaki and Yusuke Moritoh
Journal of Pharmacology and Experimental Therapeutics June 11, 2019, jpet.118.255885; DOI: https://doi.org/10.1124/jpet.118.255885
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