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Pharmacological Evaluation of SKL-18287, a New Long-Acting Glucagon-Like Peptide-1 Receptor Agonist with Enhanced Aggregation Propensity, in Rodent Models

  • Mitsuaki Takeuchi
  • Masayuki Okamoto
  • Nobuhide Watanabe
Article
  • 24 Downloads

Abstract

Very recently, we have reported a new glucagon-like peptide-1 (GLP-1) receptor agonist, SKL-18287, (EC50: 1.2 and 0.13 nM for mouse and human, respectively) with extended in vivo half-life (T1/2: 5.8 h in rats), which is a medium-sized oligopeptide comprised of only natural l-amino acids. SKL-18287 is believed to exist in oligomeric form in vivo with a molecular weight of approximately 40,000 Da, which accounts for its extended in vivo half-life. This unique property may set SKL-18287 apart from other marketed GLP-1-based drugs. In this study, we report the pharmacological effects of SKL-18287 on type 2 diabetes mellitus (T2DM) and gastric emptying (GE) in several animal models. In intraperitoneal glucose tolerance tests, SKL-18287 lowered blood glucose level in a dose-dependent manner. Significant differences were observed between the control- and SKL-18287-treated groups at 0–1 h after the 1st and 2nd glucose loading. SKL-18287 glucose-lowering effect was virtually the same for both glucose loadings. In non-obese type 2 diabetic Goto-Kakizaki (GK) rats, SKL-18287, given a range of 6–12 nmol/kg/daily, produced a robust beneficial effect on glycohemoglobin (GHb). As for liraglutide, the 8 nmol/kg/daily dose failed to produce any significant effect on GHb. SKL-18287 had more potent therapeutic effects than liraglutide in GK rats, while it had marginal effect on GE. These results suggested that SKL-18287 was more pancreas-selective than liraglutide and would mitigate gastrointestinal adverse effects such as nausea and vomiting. SKL-18287 might be useful for non-obese patients with T2DM.

Keywords

Glucagon-like peptide-1 receptor agonists Gastric emptying effect Gastrointestinal side effects Pancreas-selective 

Notes

Acknowledgements

Our special thanks are to Professor Jun-ichi Miyazaki (Osaka University, Osaka, Japan) for donating MIN6 mouse insulinoma cells. We also thank Ryuji Okamoto, Tomohiro Shigemori, Hiroshi Kinoshita, Katsura Tsukamoto, Miyuki Tamura, Takayo Murase, Shinji Furuta, and Yoshiyuki Furuta for their comments and data production. Finally, we thank Chika Otani and Asako Ohara for their experimental support.

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

10989_2018_9777_MOESM1_ESM.pdf (201 kb)
Supplementary material 1 (PDF 201 KB)

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Copyright information

© Springer Nature B.V. 2018

Authors and Affiliations

  • Mitsuaki Takeuchi
    • 1
    • 2
  • Masayuki Okamoto
    • 1
  • Nobuhide Watanabe
    • 1
    • 2
  1. 1.Mie Research ParkSanwa Kagaku Kenkyusho, Co., Ltd.Inabe-cityJapan
  2. 2.Licensing & Business Development, R&D Strategy CenterSanwa Kagaku Kenkyusho, Co., Ltd.TokyoJapan

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