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  3. Discovery of novel pyridazine derivatives as glucose transporter type 4 (GLUT4) translocation activators

Discovery of novel pyridazine derivatives as glucose transporter type 4 (GLUT4) translocation activators

  • Bioorg Med Chem Lett. 2019 Jul 15;29(14):1785-1790. doi: 10.1016/j.bmcl.2019.05.013.
Takashi Tsuji 1,  Mitsuhiro Yamaguchi 2,  Junichi Kuroyanagi 2,  Shinji Furuzono 3,  Masahiro Konishi 3,  Koji Terayama 3,  Jun Tanaka 3,  Motoko Saito 4,  Yoshiyuki Kobayashi 2
Affiliations

Affiliations

  • 1 Medicinal Chemistry Research Laboratories, Daiichi Sankyo Co, Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. Electronic address: tsuji.takashi.y3@daiichisankyo.co.jp.
  • 2 Medicinal Chemistry Research Laboratories, Daiichi Sankyo Co, Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  • 3 Cardiovascular Metabolic Research Laboratories, Daiichi Sankyo Co, Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  • 4 Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co, Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
PMID: 31101471 DOI: 10.1016/j.bmcl.2019.05.013
Abstract

We report herein the synthesis and structure-activity relationships (SAR) of a series of pyridazine derivatives with the activation of glucose transporter type 4 (GLUT4) translocation. Through a cell-based phenotype screening in L6-GLUT4-myc myoblasts and functional glucose uptake assays, lead compound 1a was identified as a functional small molecule. After further derivatization, the thienopyridazine scaffold as the central ring (B-part) was revealed to have potent GLUT4 translocation activities. Consequently, we obtained promising compound 26b, which showed a significant blood glucose lowering effect in the severe diabetic mice model (10-week aged db/db mice) after oral dosing even at 10 mg/kg, implying that our pyridazine derivatives have potential to become novel therapeutic agents for diabetes mellitus.

Keywords

Diabetes; GLUT4; Glucose transporter type 4; Insulin; Pyridazine.

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