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

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.

Reduction of Renal Transport Maximum for Glucose by Inhibition of Na+-Glucose Cotransporter Suppresses Blood Glucose Elevation in Dogs

“…10,11) As we have reported previously, T-1095, an orally active inhibitor of SGLT, excretes excess plasma glucose into urine, lowers blood glucose levels, [2][3][4][5][6][7][8][9]12) and thus has therapeutic potential for treatment of diabetes mellitus. However, to date, it is not well understood how much reduction of threshold for renal glucose reabsorption is needed for decreasing blood glucose levels.…”

Assessment of Remogliflozin Etabonate, a Sodium-Dependent Glucose Co-Transporter-2 Inhibitor, as a Perpetrator of Clinical Drug Interactions: A Study on Drug Transporters and Metabolic Enzymes

“…A number of small molecule SGLT2 inhibitors are/have been under clinical development, including the first orally absorbable SGLT inhibitor T-1095 [26], sergliflozin etabonate (GW868682) [27,28], remogliflozin etabonate (GSK189075) [14], and dapagliflozin (BMS-512148) [29,30]. Remogliflozin etabonate is a novel member of the beta-D-glucopyranoside class of SGLT2 inhibitors with in vitro Ki values near 12 nM [15].…”

Synthesis and antimicrobial evaluation of carbohydrate and polyhydroxylated non-carbohydrate fatty acid ester and ether derivatives

“…It was then dried 15 over anhydrous MgSO 4 , and concentrated under reduced pressure. 23 The crude 16 product was dissolved in DMF anhydrous (50 mL) and cooled to 0 o C. NaH (5 g, 125 17 mmol) was added portion wise, BnBr (9 mL, 75 mmol) was added and the mixture 18 was allowed to warm to room temperature and stir for 24 h. MeOH (50 mL) was 19 added to quench the mixture which was stirred for 1 h. The fully protected sugar was 20 then concentrated in vacuo and dissolved in EtOAc. The solution was washed with 21 water, dried over anhydrous MgSO 4 , and concentrated under diminished pressure.…”

“…23 The TIPS protected crude residue was then split in two and half was 25 dissolved in DMF anhydrous (30 mL) and THF anhydrous (20 mL). This solution 1 was then added dropwise at 0 o C to a suspension of NaH (2.5 g, 62.5 mmol) in DMF 2 anhydrous (10 mL) and THF anhydrous (7 mL), paramethoxybenzyl chloride (17 mL, 3 125 mmol) and tetrabutylammonium iodide (18.5 g, 50 mmol).…”