Discovery of a potent, low-absorbable sodium-dependent glucose cotransporter 1 (SGLT1) inhibitor (TP0438836) for the treatment of type 2 diabetes

  • Bioorg Med Chem Lett. 2018 Dec 1;28(22):3534-3539. doi: 10.1016/j.bmcl.2018.09.035.
Shoichi Kuroda  1 ,  Yohei Kobashi  2 ,  Takahiro Oi  3 ,  Hideaki Amada  4 ,  Lisa Okumura-Kitajima  5 ,  Fusayo Io  6 ,  Koji Yamamto  5 ,  Hiroyuki Kakinuma  7
Affiliations
  • 1. Chemistry Laboratories, Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Kita-ku, Saitama 331-9530, Japan. Electronic address: [email protected].
  • 2. Chemistry Laboratories, Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Kita-ku, Saitama 331-9530, Japan.
  • 3. Pharmaceutical Science Laboratories, Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Kita-ku, Saitama 331-9530, Japan.
  • 4. Development Management, Taisho Pharmaceutical Co., Ltd., 3-24-1, Takada, Toshima-ku, Tokyo 170-8633, Japan.
  • 5. Pharmacology Laboratories, Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Kita-ku, Saitama 331-9530, Japan.
  • 6. Medical Affairs Group, Taisho Toyama Pharmaceutical Co., 3-25-1, Takada, Toshima-ku, Tokyo 170-8635, Japan.
  • 7. Chemistry Laboratories, Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Kita-ku, Saitama 331-9530, Japan. Electronic address: [email protected].
PMID: 30297284 DOI: 10.1016/j.bmcl.2018.09.035
Abstract

The design and synthesis of a novel class of low-absorbable SGLT1 inhibitors are described. To achieve low absorption in the new series, we performed an optimization study based on a strategy to increase TPSA. Fortunately, the optimization of an aglycon moiety and a side chain of the distal aglycon moiety led to the identification of compound 30b as a potent and low-absorbable SGLT1 Inhibitor. Compound 30b showed a desirable PK profile in Sprague-Dawley (SD) rats and a favorable glucose-lowering effect in diabetic rats.

Keywords
Diabetes; Low-absorbable; SGLT1; SGLT1 inhibitor; TPSA.
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