Discovery of potent, low-absorbable sodium-dependent glucose cotransporter 1 (SGLT1) inhibitor SGL5213 for type 2 diabetes treatment

Shoichi Kuroda; Yohei Kobashi; Takahiro Oi; Kenichi Kawabe; Fumiyasu Shiozawa; Lisa Okumura-Kitajima; Mami Sugisaki-Kitano; Fusayo Io; Koji Yamamoto; Hiroyuki Kakinuma

doi:10.1016/j.bmc.2018.12.015

Discovery of potent, low-absorbable sodium-dependent glucose cotransporter 1 (SGLT1) inhibitor SGL5213 for type 2 diabetes treatment

Bioorg Med Chem. 2019 Jan 15;27(2):394-409. doi: 10.1016/j.bmc.2018.12.015. Epub 2018 Dec 11.

Affiliations

¹ Chemistry Laboratories, Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Kita-ku, Saitama 331-9530, Japan.
² Pharmaceutical Science Laboratories, Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Kita-ku, Saitama 331-9530, Japan.
³ Pharmacology Laboratories, Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Kita-ku, Saitama 331-9530, Japan.
⁴ Medical Affairs Group, Taisho Toyama Pharmaceutical Co., 3-25-1 Takada, Toshima-ku, Tokyo 170-8635, Japan.

PMID: 30579799
DOI: 10.1016/j.bmc.2018.12.015

Abstract

A new series of C-phenyl d-glucitol derivatives was designed and synthesized, and their SGLT1 inhibitory potency and absorbability were evaluated. We also investigated whether kidney drug retention could be avoided by creating molecules with different excretion pathways. To achieve a class of molecules with low absorption and that were excreted in bile, optimized synthesis was performed to bring the ClogP value and the topological polar surface area to within the appropriate ranges. Compounds 34d and 34j were poorly absorbed, but the absorbed compounds were mainly excreted in bile. Thus, smaller amounts of persistent residue in the kidneys were observed. Since 34d exerted a glucose-lowering effect at a dose of 0.3 mg/kg (p.o.) in SD rats, this compound (SGL5213) could be a clinical candidate for the treatment of type 2 diabetes.

MeSH terms

Animals
CHO Cells
Cricetulus
Humans
Hypoglycemic Agents / chemical synthesis
Hypoglycemic Agents / pharmacokinetics
Hypoglycemic Agents / pharmacology
Hypoglycemic Agents / therapeutic use*
Kidney / metabolism
Male
Molecular Structure
Rats, Sprague-Dawley
Sodium-Glucose Transporter 1 / antagonists & inhibitors*
Sodium-Glucose Transporter 2 / metabolism
Sodium-Glucose Transporter 2 Inhibitors / chemical synthesis
Sodium-Glucose Transporter 2 Inhibitors / pharmacokinetics
Sodium-Glucose Transporter 2 Inhibitors / pharmacology
Sodium-Glucose Transporter 2 Inhibitors / therapeutic use
Sorbitol / analogs & derivatives*
Sorbitol / chemical synthesis
Sorbitol / pharmacokinetics
Sorbitol / pharmacology
Sorbitol / therapeutic use
Structure-Activity Relationship

Substances

Hypoglycemic Agents
SGL5213
SLC5A1 protein, human
SLC5A2 protein, human
Sodium-Glucose Transporter 1
Sodium-Glucose Transporter 2
Sodium-Glucose Transporter 2 Inhibitors
Sorbitol