Na(+)-glucose cotransporter (SGLT) inhibitors as antidiabetic agents. 4. Synthesis and pharmacological properties of 4'-dehydroxyphlorizin derivatives substituted on the B ring

J Med Chem. 1999 Dec 30;42(26):5311-24. doi: 10.1021/jm990175n.

Abstract

In our studies of Na(+)-glucose cotransporter (SGLT) inhibitors as antidiabetic agents, a series of novel 4'-dehydroxyphlorizin derivatives substituted on the B ring was prepared and their effects on urinary glucose excretion were evaluated in rats. Introduction of only a small alkyl group at the 4'-position increased the activity, and 3-(benzo¿bfuran-5-yl)-2',6'-dihydroxy-4'-methylpropiophenone 2'-O-beta-D-glucopyranoside (4) showed the most potent effect. To overcome hydrolysis of compound 4 by beta-glucosidase in the digestive tract, the OH groups on the glucose moiety of compound 4 were modified. Three prodrugs (5, 42, and 55) were more potent than the parent compound 4 by oral administration, and finally 3-(benzo¿bfuran-5-yl)-2',6'-dihydroxy-4'-methylpropiophenone 2'-O-(6-O-methoxycarbonyl-beta-D-glucopyranoside) (5) was selected as a new promising candidate. Compound 5 was metabolized mainly by liver esterase to the active form (4), which was about 10 times more potent than 5 in inhibiting SGLT. In oral glucose tolerance test in db/db mice, compound 5 dose-dependently suppressed the elevation of glucose levels. Single administration of 5 reduced hyperglycemia concurrently with increase of glucose excretion into urine in diabetic KK-A(y) mice. Furthermore, compound 5 suppressed the elevation of blood glucose levels but did not lower it below the normal level even in fasted conditions in KK-A(y) mice. Additionally, long-term treatment with 5 dose-dependently reduced hyperglycemia and HbA1c in KK-A(y) mice. These pharmacological data strongly suggest that compound 5 has a therapeutic potential in the treatment of NIDDM.

MeSH terms

  • Animals
  • Biotransformation
  • Blood Glucose / analysis
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Dogs
  • Glucose / chemical synthesis*
  • Glucose / pharmacology*
  • Glucose / therapeutic use
  • Glycated Hemoglobin A / analysis
  • Haplorhini
  • Humans
  • Hypoglycemic Agents / chemical synthesis
  • Hypoglycemic Agents / pharmacology*
  • Hypoglycemic Agents / therapeutic use
  • Male
  • Membrane Glycoproteins / antagonists & inhibitors*
  • Mice
  • Monosaccharide Transport Proteins / antagonists & inhibitors*
  • Rats
  • Rats, Sprague-Dawley
  • Sodium-Glucose Transporter 1
  • Spectrum Analysis
  • Structure-Activity Relationship

Substances

  • 4'-dehydroxyphlorizin
  • Blood Glucose
  • Glycated Hemoglobin A
  • Hypoglycemic Agents
  • Membrane Glycoproteins
  • Monosaccharide Transport Proteins
  • SLC5A1 protein, human
  • Slc5a1 protein, mouse
  • Slc5a1 protein, rat
  • Sodium-Glucose Transporter 1
  • Glucose