Na(+)-glucose cotransporter inhibitors as antidiabetic agents. III. Synthesis and pharmacological properties of 4'-dehydroxyphlorizin derivatives modified at the OH groups of the glucose moiety.
To overcome hydrolysis by beta-glucosidase present in the digestive tract, the OH groups on the glucose moiety of the 4'-dehydroxyphlorizin derivatives (1, 2, 3) were modified with various kinds of patterns, and then the effects of the modified compounds on urinary glucose excretion were evaluated in rats. Among them, triacetyl (9), 2,3-O-diacetyl (17), 6-O-methoxycarbonyl (34), 4-O-methoxycarbonyl (38), and 2-O-acetyl (41) derivatives showed more potent effect than the parent compound 2 by oral administration (p.o.). The stabilities of the compounds 34, 38, and 41 against beta-glucosidase were higher than that of 2. The increase in oral activity was found to correlate with the enhancement of the stability against beta-glucosidase.
Hongu
M
M
Discovery Research Laboratory, Tanabe Seiyaku Co. Ltd., Saitama, Japan.
Funami
N
N
Takahashi
Y
Y
Saito
K
K
Arakawa
K
K
Matsumoto
M
M
Yamakita
H
H
Tsujihara
K
K
D000818:Animals; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004285:Dogs; D005947:Glucose / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006029:Glycosuria / Q000378:metabolism; D006868:Hydrolysis; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D009004:Monosaccharide Transport Proteins / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000378:metabolism; D051269:Sodium-Glucose Transporter 1
C115838:4'-dehydroxyphlorizin; D007004:Hypoglycemic Agents; D008562:Membrane Glycoproteins; D009004:Monosaccharide Transport Proteins; C495676:Slc5a1 protein, rat; D051269:Sodium-Glucose Transporter 1; D012964:Sodium; D005947:Glucose