title: LP-925219 maximizes urinary glucose excretion in mice by inhibiting both renal SGLT1 and SGLT2.
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.
authors.affiliation: Lexicon Pharmaceuticals Inc. The Woodlands, Texas.
authors.forename: David R
authors.initials: DR
authors.lastname: Powell
authors.affiliation: Lexicon Pharmaceuticals Inc. The Woodlands, Texas.
authors.forename: Melinda G
authors.initials: MG
authors.lastname: Smith
authors.affiliation: Lexicon Pharmaceuticals Inc. The Woodlands, Texas.
authors.forename: Deon D
authors.initials: DD
authors.lastname: Doree
authors.affiliation: Lexicon Pharmaceuticals Inc. The Woodlands, Texas.
authors.forename: Angela L
authors.initials: AL
authors.lastname: Harris
authors.affiliation: Lexicon Pharmaceuticals Inc. The Woodlands, Texas.
authors.forename: Wendy W
authors.initials: WW
authors.lastname: Xiong
authors.affiliation: Lexicon Pharmaceuticals Inc. The Woodlands, Texas.
authors.forename: Faika
authors.initials: F
authors.lastname: Mseeh
authors.affiliation: Lexicon Pharmaceuticals Inc. The Woodlands, Texas.
authors.forename: Alan
authors.initials: A
authors.lastname: Wilson
authors.affiliation: Lexicon Pharmaceuticals Inc. The Woodlands, Texas.
authors.forename: Suma
authors.initials: S
authors.lastname: Gopinathan
authors.affiliation: Lexicon Pharmaceuticals Inc. The Woodlands, Texas.
authors.forename: Damaris
authors.initials: D
authors.lastname: Diaz
authors.affiliation: Lexicon Pharmaceuticals Inc. Princeton, New Jersey.
authors.forename: Nicole C
authors.initials: NC
authors.lastname: Goodwin
authors.affiliation: Lexicon Pharmaceuticals Inc. Princeton, New Jersey.
authors.forename: Bryce
authors.initials: B
authors.lastname: Harrison
authors.affiliation: Lexicon Pharmaceuticals Inc. Princeton, New Jersey.
authors.forename: Eric
authors.initials: E
authors.lastname: Strobel
authors.affiliation: Lexicon Pharmaceuticals Inc. Princeton, New Jersey.
authors.forename: David B
authors.initials: DB
authors.lastname: Rawlins
authors.affiliation: Lexicon Pharmaceuticals Inc. Princeton, New Jersey.
authors.forename: Ken
authors.initials: K
authors.lastname: Carson
authors.affiliation: Lexicon Pharmaceuticals Inc. The Woodlands, Texas.
authors.forename: Brian
authors.initials: B
authors.lastname: Zambrowicz
authors.affiliation: Lexicon Pharmaceuticals Inc. The Woodlands, Texas.
authors.forename: Zhi-Ming
authors.initials: ZM
authors.lastname: Ding
keywords: Diabetes; SGLT1; SGLT2; knockout mice; small molecule; urinary glucose excretion