Synthesis and biological evaluation of benzocyclobutane-C-glycosides as potent and orally active SGLT1/SGLT2 dual inhibitors

Bioorg Med Chem Lett. 2018 Apr 15;28(7):1182-1187. doi: 10.1016/j.bmcl.2018.02.057. Epub 2018 Mar 1.

Abstract

Synthesis and biological evaluation of benzocyclobutane-C-glycosides as potent and orally active SGLT1/SGLT2 dual inhibitors are described. Compound 19 showed high inhibitory potency at SGLT1 (IC50 = 45 nM), and excellent potency at SGLT2 (IC50 = 1 nM). It also displayed excellent PK profiles in mice, rats, dogs and monkeys (F = 78-107%). In SD rats, compound 19 treatments significantly reduced blood glucose levels in a dose-dependent manner. In ZDF rats, compound 19 displayed anti-hyperglycemic effect up to 24 h. Therefore, compound 19 may serve as valuable pharmacological tool, and potential use as a treatment for metabolic syndrome.

Keywords: Anti-hyperglycemic effect; Benzocyclobutane-C-glycosides; SGLT1/2 dual inhibitor.

MeSH terms

  • Administration, Oral
  • Animals
  • Benzene Derivatives / administration & dosage
  • Benzene Derivatives / chemistry
  • Benzene Derivatives / pharmacology*
  • Cyclobutanes / administration & dosage
  • Cyclobutanes / chemistry
  • Cyclobutanes / pharmacology*
  • Dogs
  • Dose-Response Relationship, Drug
  • Glycosides / administration & dosage
  • Glycosides / chemistry
  • Glycosides / pharmacology*
  • Haplorhini
  • Humans
  • Mice
  • Molecular Structure
  • Rats
  • Sodium-Glucose Transporter 1 / antagonists & inhibitors*
  • Sodium-Glucose Transporter 1 / metabolism
  • Sodium-Glucose Transporter 2 / metabolism
  • Sodium-Glucose Transporter 2 Inhibitors*
  • Structure-Activity Relationship

Substances

  • Benzene Derivatives
  • Cyclobutanes
  • Glycosides
  • Sodium-Glucose Transporter 1
  • Sodium-Glucose Transporter 2
  • Sodium-Glucose Transporter 2 Inhibitors