Discovery of DS-1150b, a novel xanthene compound for activating GLUT4 translocation

  • Bioorg Med Chem Lett. 2025 Jul 1:122:130191. doi: 10.1016/j.bmcl.2025.130191.
Masaki Meguro  1 ,  Fuminao Doi  2 ,  Tsuyoshi Soneda  3 ,  Shinji Furuzono  2 ,  Masahiro Konishi  4 ,  Jun Harada  2 ,  Jun Tanaka  2 ,  Shinichi Inoue  5 ,  Makoto Ono  6 ,  Katsuji Kagechika  2
Affiliations
  • 1. Shinagawa R&D Center, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. Electronic address: [email protected].
  • 2. Shinagawa R&D Center, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  • 3. Process Technology Research Laboratories, Technology Division, Daiichi Sankyo Co., Ltd., 1-12-1 Shinomiya, Hiratsuka-shi, Kanagawa 254-0014, Japan.
  • 4. DS Corporate Strategy Department, Daiichi Sankyo Co., Ltd., 3-5-1 Nihonbashi-Honcho, Chuo-ku, Tokyo 103-8426, Japan.
  • 5. Daiichi Sankyo Inc., 211 Mt. Airy Road, Basking Ridge, NJ 07920, USA.
  • 6. Quality Assurance Department, Daiichi Sankyo Co., Ltd., 3-5-1 Nihonbashi-Honcho, Chuo-ku, Tokyo 103-8426, Japan.
PMID: 40122472 DOI: 10.1016/j.bmcl.2025.130191
Abstract

The glucose transporter 4 (GLUT4) is a high-affinity glucose transporter that is predominantly expressed in the skeletal muscle, myocardium, and adipose tissue, and is the rate-limiting transporter of insulin-stimulated glucose uptake. Compounds that enhance the process of GLUT4 translocation in skeletal muscle would provide a novel treatment for type 2 diabetes mellitus. After a high-throughput screening (HTS) campaign and medicinal chemistry efforts, we identified the xanthene compound DS-1150b (16·tBuNH2) as a novel potent GLUT4 translocation enhancer. DS-1150b was found to promote GLUT4 translocation in L6-myotubes in rats and showed a glucose-lowering effect in an oral glucose tolerance test (oGTT) in a Zucker fatty rat model. Identification of naphthalene analog DS20060511 is also briefly described.

Keywords
DS-1150b; DS20060511; GLUT4; Glucose transporter 4; Translocation activator; Type 2 diabetes mellitus; Xanthene compound.
Products