- Propiophenone derivatives and process for preparing the same
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A propiophenone derivative of the formula (I): wherein OX is a hydroxy group which may optionally be protected, Y is a lower alkyl group, and Z is a beta -D-glucopyranosyl group wherein one or more hydroxy groups may optionally be protected, or a pharmace
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- Na+-glucose cotransporter (SGLT) inhibitors as antidiabetic agents. 4. Synthesis and pharmacological properties of 4'- dehydroxyphlorizin derivatives substituted on the B ring
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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-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.
- Tsujihara, Kenji,Hongu, Mitsuya,Saito, Kunio,Kawanishi, Hiroyuki,Kuriyama, Kayoko,Matsumoto, Mamoru,Akira, Oku,Ueta, Kiichiro,Tsuda, Minoru,Saito, Akira
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p. 5311 - 5324
(2007/10/03)
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