Na(+)-glucose cotransporter inhibitors as antidiabetics. I. Synthesis and pharmacological properties of 4'-dehydroxyphlorizin derivatives based on a new concept.
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.
Tsujihara
K
K
Lead Optimization Research Laboratory, Tanabe Seiyaku Co., Ltd., Saitama, Japan.
Hongu
M
M
Saito
K
K
Inamasu
M
M
Arakawa
K
K
Oku
A
A
Matsumoto
M
M
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D051272:Glucose Transporter Type 1; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D066298:In Vitro Techniques; D007408:Intestinal Absorption / Q000187:drug effects; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D008871:Microvilli / Q000378:metabolism; D009004:Monosaccharide Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010695:Phlorhizin / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D051269:Sodium-Glucose Transporter 1
D001786:Blood Glucose; D051272:Glucose Transporter Type 1; D007004:Hypoglycemic Agents; D008562:Membrane Glycoproteins; D009004:Monosaccharide Transport Proteins; C495677:SLC2A1 protein, human; C495674:SLC5A1 protein, human; C495678:Slc2a1 protein, mouse; C495679:Slc2a1 protein, rat; C495675:Slc5a1 protein, mouse; C495676:Slc5a1 protein, rat; D051269:Sodium-Glucose Transporter 1; D010695:Phlorhizin; D005947:Glucose