Aglycone exploration of C-arylglucoside inhibitors of renal sodium-dependent glucose transporter SGLT2

Ellsworth, Bruce A.; Meng, Wei; Patel, Manorama; Girotra, Ravindar N.; Wu, Gang; Sher, Philip M.; Hagan, Deborah; Obermeier, Mary; Humphreys, W. Griffith; Robertson, James G.; Wang, Aiying; Han, Song‐Ping; Waldron, Thomas L.; Morgan, Nathan; Whaley, Jean M.; Washburn, William N.

doi:10.1016/j.bmcl.2008.07.109

Cited by 55 publications

(23 citation statements)

References 27 publications

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“…Remogliflozin etabonate, the prodrug of remogliflozin, is a novel member of the ␤-D-glucopyranoside class of SGLT2 inhibitors. Like other members of this class, remogliflozin was developed as a prodrug to enhance oral absorption and reduce the susceptibility to glycosidase degradation (Ellsworth et al, 2008;Washburn, 2009). Remogliflozin is the active entity with an in vitro IC 50 value of 12.4 nM (Fujimori et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Assessment of the Drug Interaction Risk for Remogliflozin Etabonate, a Sodium-Dependent Glucose Cotransporter-2 Inhibitor: Evidence from In Vitro, Human Mass Balance, and Ketoconazole Interaction Studies

et al. 2012

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ABSTRACT:Remogliflozin etabonate is the ester prodrug of remogliflozin, a selective sodium-dependent glucose cotransporter-2 inhibitor. This work investigated the absorption, metabolism, and excretion of [ A ketoconazole clinical drug interaction study, along with the human mass balance findings, confirmed that CYP3A4 contributes less than 50% to remogliflozin metabolism, demonstrating that other enzyme pathways (e.g., P450s, UDP-glucuronosyltransferases, and glucosidases) make significant contributions to the drug's clearance. Overall, these studies support a low clinical drug interaction risk for remogliflozin etabonate due to the availability of multiple biotransformation pathways.

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Section: Discussionmentioning

confidence: 99%

Assessment of the Drug Interaction Risk for Remogliflozin Etabonate, a Sodium-Dependent Glucose Cotransporter-2 Inhibitor: Evidence from In Vitro, Human Mass Balance, and Ketoconazole Interaction Studies

et al. 2012

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“…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].…”

Section: Discussionmentioning

confidence: 99%

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

Joseph¹

2012

J Diabetes Metab

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Type 2 diabetes mellitus is a chronic disease characterized by progressive deterioration of glycemic control and an increased risk of associated complications. Remogliflozin etabonate is the ester prodrug of remogliflozin, a selective sodium-dependent glucose transporter-2 inhibitor that was under development to treat type 2 diabetes. This work investigated the in vitro inhibition of efflux and uptake transporters and cytochrome P450 enzymes by remogliflozin etabonate, remogliflozin and a number of other metabolites. As well, the ability of remogliflozin to induce cytochrome P450 enzymes in human hepatocytes was examined. Remogliflozin etabonate, remogliflozin and GSK279782 (an active pharmacological metabolite of remogliflozin) were inhibitors of organic anion transporting polypeptide-1B1 with IC 50 values of 5.3, 25 and 14 µM, respectively. Remogliflozin etabonate and remogliflozin were inhibitors of organic cation transporter-1 with IC 50 values of 43 and 39 µM, respectively. In contrast, remogliflozin etabonate, remogliflozin, GSK279782, and GSK333081 (a metabolite of remogliflozin) were not inhibitors of P-glycoprotein, a number of other renal transporters, or cytochrome P450 enzymes. Further, three circulating glucuronide metabolites found in human plasma were not inhibitors of cytochrome P450 enzymes or organic anion transporters. Remogliflozin etabonate, but not remogliflozin or GSK279782, activated the pregnane X Receptor in vitro. Further studies demonstrated that remogliflozin (up to 100 µM) did not induce cytochrome P450 3A4 or 1A1 mRNA in human hepatocytes; however a small increase was noted for CYP2B6 mRNA. Combined with pharmacokinetic data from healthy volunteers and diabetic subjects, these in vitro investigations provide a low drug interaction potential for remogliflozin etabonate, remogliflozin and the associated metabolites to be perpetrators of clinical drug interactions. This information has been used to guide the design of clinical studies with remogliflozin etabonate when given with other co-medications.

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“…Under the specified conditions the Et 3 SiH reduction yields almost exclusively the crystalline tetraacetoxy beta C-glucoside thereby enabling purification before alkaline hydrolysis to generate the final product as an amorphous solid. In contrast when benzyl ether protecting groups were employed, the α/β ratio was much less favorable [27]. To date, all attempts to induce crystallization of these C-aryl glucosides have failed.…”

Section: Synthetic Routementioning

confidence: 99%

Dapagliflozin, A Selective SGLT2 Inhibitor for Treatment of Diabetes

Washburn

2015

Successful Drug Discovery

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Aglycone exploration of C-arylglucoside inhibitors of renal sodium-dependent glucose transporter SGLT2

Cited by 55 publications

References 27 publications

Assessment of the Drug Interaction Risk for Remogliflozin Etabonate, a Sodium-Dependent Glucose Cotransporter-2 Inhibitor: Evidence from In Vitro, Human Mass Balance, and Ketoconazole Interaction Studies

Assessment of the Drug Interaction Risk for Remogliflozin Etabonate, a Sodium-Dependent Glucose Cotransporter-2 Inhibitor: Evidence from In Vitro, Human Mass Balance, and Ketoconazole Interaction Studies

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

Dapagliflozin, A Selective SGLT2 Inhibitor for Treatment of Diabetes

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