title: Empagliflozin, a novel selective sodium glucose cotransporter-2 (SGLT-2) inhibitor: characterisation and comparison with other SGLT-2 inhibitors.
abstract: OBJECTIVE
  Empagliflozin is a selective sodium glucose cotransporter-2 (SGLT-2) inhibitor in clinical development for the treatment of type 2 diabetes mellitus. This study assessed pharmacological properties of empagliflozin in vitro and pharmacokinetic properties in vivo and compared its potency and selectivity with other SGLT-2 inhibitors.
  
  
  METHODS
  [(14)C]-alpha-methyl glucopyranoside (AMG) uptake experiments were performed with stable cell lines over-expressing human (h) SGLT-1, 2 and 4. Two new cell lines over-expressing hSGLT-5 and hSGLT-6 were established and [(14)C]-mannose and [(14)C]-myo-inositol uptake assays developed. Binding kinetics were analysed using a radioligand binding assay with [(3)H]-labelled empagliflozin and HEK293-hSGLT-2 cell membranes. Acute in vivo assessment of pharmacokinetics was performed with normoglycaemic beagle dogs and Zucker diabetic fatty (ZDF) rats.
  
  
  RESULTS
  Empagliflozin has an IC(50) of 3.1 nM for hSGLT-2. Its binding to SGLT-2 is competitive with glucose (half-life approximately 1 h). Compared with other SGLT-2 inhibitors, empagliflozin has a high degree of selectivity over SGLT-1, 4, 5 and 6. Species differences in SGLT-1 selectivity were identified. Empagliflozin pharmacokinetics in ZDF rats were characterised by moderate total plasma clearance (CL) and bioavailability (BA), while in beagle dogs CL was low and BA was high.
  
  
  CONCLUSIONS
  Empagliflozin is a potent and competitive SGLT-2 inhibitor with an excellent selectivity profile and the highest selectivity window of the tested SGLT-2 inhibitors over hSGLT-1. Empagliflozin represents an innovative therapeutic approach to treat diabetes.
authors: CardioMetabolic Diseases Research, Boehringer Ingelheim Pharma GmbH & Co.KG, Biberach, Germany. rolf.grempler@boehringer-ingelheim.com
authors: R
authors: R
authors: Grempler
authors: L
authors: L
authors: Thomas
authors: M
authors: M
authors: Eckhardt
authors: F
authors: F
authors: Himmelsbach
authors: A
authors: A
authors: Sauer
authors: D E
authors: DE
authors: Sharp
authors: R A
authors: RA
authors: Bakker
authors: M
authors: M
authors: Mark
authors: T
authors: T
authors: Klein
authors: P
authors: P
authors: Eickelmann
mesh_terms: D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D001786:Blood Glucose / Q000187:drug effects*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D004285:Dogs; D005960:Glucosides / Q000494:pharmacology*; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D009004:Monosaccharide Transport Proteins / Q000097:blood / Q000187:drug effects*; D051381:Rats; D011924:Rats, Zucker; D000077203:Sodium-Glucose Transporter 2 Inhibitors
chemical_list: D001559:Benzhydryl Compounds; D001786:Blood Glucose; D005960:Glucosides; D007004:Hypoglycemic Agents; D009004:Monosaccharide Transport Proteins; D000077203:Sodium-Glucose Transporter 2 Inhibitors; C570240:empagliflozin