Na(+)-glucose cotransporter inhibitors as antidiabetics. I. Synthesis and pharmacological properties of 4'-dehydroxyphlorizin derivatives based on a new concept

Chem Pharm Bull (Tokyo). 1996 Jun;44(6):1174-80. doi: 10.1248/cpb.44.1174.


Based on our new concept that inhibitors of the Na(+)-glucose cotransporter (SGLT) would be useful as antidiabetics, 4'-dehydroxyphlorizin derivatives 1a--f were designed, synthesized, and examined for various pharmacological properties related to antidiabetic activity. In normal rats, 1a, e and phlorizin showed a strong SGLT-inhibitory effect and significantly increased urinary glucose on intraperitoneal administration at 10 mg/kg, though only 1a resulted in excretion of large quantities of urinary glucose on oral administration at 100 mg/kg. Compounds 1a, e, and phlorizin markedly inhibited glucose uptake in the small intestine during enteric perfusion in normal rats. Compound 1a had a significant reducing effect on blood glucose in the glucose tolerance test in mice when administered orally and also lowered blood glucose in streptozotocin-induced diabetic rats. The aglycons 2a, e of 1a, e, and 1a showed weak inhibitory effects on the facilitated glucose transporter-1 (GLUT-1) in human erythrocytes, while phloretin had a strong inhibitory effect on GLUT-1. Compound 1a caused no apparent renal damage in rats when administered orally at 1 g/kg for 4 successive weeks. Thus, 1a was considered to be a promising candidate as a lead compound for antidiabetics of a new type, and was selected for further pharmacological evaluation.

MeSH terms

  • Animals
  • Blood Glucose / metabolism
  • Diabetes Mellitus, Experimental / metabolism
  • Erythrocytes / drug effects
  • Erythrocytes / metabolism
  • Glucose / metabolism
  • Glucose Transporter Type 1
  • Humans
  • Hypoglycemic Agents / chemical synthesis*
  • Hypoglycemic Agents / pharmacology
  • In Vitro Techniques
  • Intestinal Absorption / drug effects
  • Intestine, Small / drug effects
  • Intestine, Small / metabolism
  • Kidney / drug effects
  • Kidney / metabolism
  • Male
  • Membrane Glycoproteins / antagonists & inhibitors*
  • Membrane Glycoproteins / metabolism
  • Mice
  • Mice, Inbred Strains
  • Microvilli / metabolism
  • Monosaccharide Transport Proteins / antagonists & inhibitors*
  • Monosaccharide Transport Proteins / metabolism
  • Phlorhizin / analogs & derivatives
  • Phlorhizin / chemical synthesis*
  • Phlorhizin / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Sodium-Glucose Transporter 1


  • Blood Glucose
  • Glucose Transporter Type 1
  • Hypoglycemic Agents
  • Membrane Glycoproteins
  • Monosaccharide Transport Proteins
  • SLC2A1 protein, human
  • SLC5A1 protein, human
  • Slc2a1 protein, mouse
  • Slc2a1 protein, rat
  • Slc5a1 protein, mouse
  • Slc5a1 protein, rat
  • Sodium-Glucose Transporter 1
  • Phlorhizin
  • Glucose