LP‐925219 maximizes urinary glucose excretion in mice by inhibiting both renal SGLT1 and SGLT2. Issue 2 (31st March 2015)

• Record Type: Journal Article
• Authors: Powell, David R.; Smith, Melinda G.; Doree, Deon D.; Harris, Angela L.; Xiong, Wendy W.; Mseeh, Faika; Wilson, Alan; Gopinathan, Suma; Diaz, Damaris; Goodwin, Nicole C.; Harrison, Bryce; Strobel, Eric; Rawlins, David B.; Carson, Ken; Zambrowicz, Brian; Ding, Zhi‐Ming
• Is Part Of: Pharmacology research & perspectives. Volume 3:Issue 2(2015:Apr.)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2015-03-31
• Subjects: Diabetes -- knockout mice -- SGLT1 -- SGLT2 -- small molecule -- urinary glucose excretion; Pharmacology -- Periodicals; Drug development -- Periodicals; 615.105
• DOI: 10.1002/prp2.129
• Languages: English
• ISSNs: 2052-1707

Abstract

Abstract: Sodium‐glucose cotransporter 2 (SGLT2) inhibitors are a new class of oral anti‐diabetic agents that improve glycemic control by inhibiting SGLT2‐mediated renal glucose reabsorption. Currently available agents increase urinary glucose excretion (UGE) to <50% of maximal values because they do not inhibit SGLT1, which reabsorbs >50% of filtered glucose when SGLT2 is completely inhibited. This led us to test whether LP‐925219, a small molecule dual SGLT1/SGLT2 inhibitor, increases UGE to maximal values in wild‐type (WT) mice. We first tested LP‐925219 inhibition of glucose transport by HEK293 cells expressing SGLT1 or SGLT2, and then characterized LP‐925219 pharmacokinetics. We found that LP‐925219 was a potent inhibitor of mouse SGLT1 (IC50 = 22.6 nmol/L) and SGLT2 (IC50 = 0.5 nmol/L), and that a 10 mg/kg oral dose was bioavailable (87%) with a long half‐life (7 h). We next delivered LP‐925219 by oral gavage to WT, SGLT1 knockout (KO), SGLT2 KO, and SGLT1/SGLT2 double KO (DKO) mice and measured their 24‐h UGE. We found that, in vehicle‐treated mice, DKO UGE was maximal and SGLT2 KO, SGLT1 KO, and WT UGEs were 30%, 2%, and 0.2% of maximal, respectively; we also found that LP‐925219 dosed at 60 mg/kg twice daily increased UGE of SGLT1 KO, SGLT2 KO, and WT mice to DKO UGE levels. These findings show that orally available dual SGLT1/SGLT2 inhibitors can maximize 24‐h UGE in mammals, and suggest that such agents merit further evaluation for their potential, in diabetic patients, to achieve better glycemic control than is achieved using selective SGLT2 inhibitors. Abstract : e00129