Na+-Glucose Cotransporter (SGLT) Inhibitors as Antidiabetic Agents. 4. Synthesis and Pharmacological Properties of 4‘-Dehydroxyphlorizin Derivatives Substituted on the B Ring

• Published in: Journal of medicinal chemistry 1999-12, Vol.42 (26), p.5311-5324
• Main Authors: Tsujihara, Kenji, Hongu, Mitsuya, Saito, Kunio, Kawanishi, Hiroyuki, Kuriyama, Kayoko, Matsumoto, Mamoru, Oku, Akira, Ueta, Kiichiro, Tsuda, Minoru, Saito, Akira
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Biotransformation; Blood Glucose - analysis; Diabetes Mellitus, Type 2 - drug therapy; Dogs; General and cellular metabolism. Vitamins; 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; Medical sciences; Membrane Glycoproteins - antagonists & inhibitors; Mice; Monosaccharide Transport Proteins - antagonists & inhibitors; Pharmacology. Drug treatments; Rats; Rats, Sprague-Dawley; Sodium-Glucose Transporter 1; Spectrum Analysis; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm990175n

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[b]furan-5-yl)-2‘,6‘-dihydroxy-4‘-methylpropiophenone 2‘-O-β-d-glucopyranoside (4) showed the most potent effect. To overcome hydrolysis of compound 4 by β-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[b]furan-5-yl)-2‘,6‘-dihydroxy-4‘-methylpropiophenone 2‘-O-(6-O-methoxycarbonyl-β-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-Ay 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-Ay mice. Additionally, long-term treatment with 5 dose-dependently reduced hyperglycemia and HbA1c in KK-Ay mice. These pharmacological data strongly suggest that compound 5 has a therapeutic potential in the treatment of NIDDM.