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Empagliflozin, a Novel Selective Sodium Glucose Cotransporter2

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Empagliflozin, a Novel Selective Sodium Glucose Cotransporter2 Diabetes, Obesity and Metabolism 14: 83–90, 2012. original article © 2011 Blackwell Publishing Ltd Empagliflozin, a novel selective sodium glucose cotransporter-2 (SGLT-2) inhibitor: characterisation and comparison with other SGLT-2 inhibitors 1∗ 1∗ 2 2 3 4 1 article R. Grempler ,L.Thomas ,M.Eckhardt , F. Himmelsbach ,A.Sauer ,D.E.Sharp , R. A. Bakker , original M. Mark1, T. Klein1 & P. Eickelmann1 1CardioMetabolic Diseases Research, Boehringer Ingelheim Pharma GmbH & Co.KG, Biberach, Germany 2Medicinal Chemistry, Boehringer Ingelheim Pharma GmbH & Co.KG, Biberach, Germany 3Drug Discovery Support, Boehringer Ingelheim Pharma GmbH & Co.KG, Biberach, Germany 4 Drug Metabolism and Pharmacokinetics, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, USA Aims: 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: [14C]-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 [14C]-mannose and [14C]-myo-inositol uptake assays developed. Binding kinetics were analysed using a radioligand binding assay with [3H]-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 IC50 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. Keywords: diabetes, empagliflozin, phlorizin, SGLT, SGLT-2 inhibitor, type 2 diabetes Date submitted 27 May 2011; date of first decision 26 June 2011; date of final acceptance 5 October 2011 Introduction Residual glucose that is not taken up by SGLT-2 is reabsorbed by another SGLT family member, SGLT-1, which has a similar Sodium glucose cotransporters (SGLTs) are involved in the affinity for glucose [3] and is located in the S3 segment of the control of steady state glycaemia through mediation of the proximal tubule [5]. In contrast to SGLT-2, SGLT-1 is also reuptake of glucose from the proximal tubules of the kidney [1], found in the intestine, heart, liver and lung, with its main and as such, their inhibition has therapeutic potential in type 2 function being glucose and galactose absorption in the small diabetes. A significant proportion of glucose reabsorption is intestine [6,7]. As a consequence, selectivity of SGLT inhibitors facilitated by SGLT-2 [1,2], a member of the SGLT family. for SGLT-2 over SGLT-1 is important, as inhibition of glucose SGLT-2 is a low affinity, high capacity glucose cotransporter reabsorption from the intestine can result in ‘glucose-galactose that is almost exclusively expressed in the kidney cortex, specifically in the apical membrane of the early proximal tubule malabsorption’, a disease characterised by severe dehydration (S1 segment) [3,4]. Inhibition of SGLT-2 has been shown to and diarrhoea seen in individuals with mutations in the SGLT-1 block the body’s capacity to reabsorb glucose via the kidney, gene [8,9]. leading to glucose elimination in the urine and a reduction in The roles of the other SGLT family members in glycaemic blood glucose levels [5]. control are less well understood. SGLT-3 is expressed in neurons of the small intestine and in neuromuscular junctions of skeletal muscle, and is not capable of monosaccharide Correspondence to: Dr Rolf Grempler, Department of CardioMetabolic Diseases Research, Boehringer Ingelheim GmbH & Co.KG, Birkendorfer Straße 65, D-88397 Biberach an der transport, but transports sodium upon glucose binding [10]. Riss, Germany. Three other SGLTs, SGLT-4, 5 and 6, are expressed in the E-mail: [email protected] kidney and potentially play a role in renal monosaccharide ∗Both authors contributed equally. and/or sodium reabsorption. SGLT-4 has been shown to original article DIABETES, OBESITY AND METABOLISM transport mannose, 1,5-anhydro-D-glucitol and fructose in a sodium-dependent manner and is also highly expressed in 160 hSGLT-2 hSGLT-1 the small intestine [11]. SGLT-5 has a similar localisation to 140 hSGLT-4 SGLT-2, being exclusive to the kidney cortex, although its role 120 hSGLT-5 (mannose) 100 in monosaccharide transport is not established [12]. SGLT-6 is hSGLT-6 (myo-inositol) a high-affinity myo-inositol transporter also found in the brain 80 60 [% control] and intestine [13]. C]-AMG-uptake 40 14 The concept of SGLT-2 inhibition has been pursued by [ 20 several pharmaceutical companies, with the development of 0 -11 -10 -9 -8 -7 -6 -5 -4 T-1095 [14] (Tanabe Seiyaku, Osaka, Japan) and later aryl log empagliflozin [M] and heteroaryl O-glucosides, for example, sergliflozin [15] and remogliflozin [16] (Glaxo SmithKline, Brentwood, UK) Figure 1. Potency of empagliflozin for sodium glucose cotransporter and AVE2268 [17] (Sanofi-Aventis, Paris, France). Although (SGLT)-2 and selectivity over SGLT-1, 4, 5 and 6. Inset shows the chemical these compounds established the proof of concept in humans, structure of empagliflozin. Results show inhibition of monosaccharide their pharmacokinetic properties are probable to have pre- uptake by hSGLT-2, 1, 4, 5 and 6, respectively, at different concentrations vented their further clinical development. Today, only C- of empagliflozin. [14C]-AMG was used as substrate for hSGLT-1, 2 and 4, glucoside SGLT-2 inhibitors are in clinical development for the mannose was used as substrate for hSGLT-5 and myo-inositol for hSGLT- treatment of type 2 diabetes, including dapagliflozin [18–20] 6. Data are shown from representative experiments and are expressed as mean % of respective control ± standard error of the mean, where the (Bristol-Myers Squibb, NY, USA/AstraZeneca, London, UK), control value was measured at 10−11 M empagliflozin of each individual canagliflozin [21] (Johnson & Johnson, New Brunswick, NJ, assay. USA), empagliflozin (Boehringer Ingelheim, Ingelheim, Ger- many), ipragliflozin (Astellas, Tokyo, Japan), tofogliflozin (HEK293-hSGLT-2), hSGLT-4 (HEK293-hSGLT-4), hSGLT- (Roche, Basel, Switzerland) and TS-071 (Taisho, Tokyo, 6 (HEK293-hSGLT-2) and mouse (m) SGLT-1 (HEK293- Japan) [22]. mSGLT-1). CHO-K1 cells (ATCC) were stably transfected This manuscript presents the in vitro properties of with vectors for rat (r) SGLT-1 (CHO-rSGLT-1) and rSGLT- the potent and selective competitive SGLT-2 inhibitor 2 (CHO-rSGLT-2). T-REx 293 cells (Invitrogen) were stably empagliflozin in comparison with other SGLT inhibitors and transfected with a vector for hSGLT-5 (T-REx 293-hSGLT-5). its pharmacokinetic profile in rats and dogs. See the Supporting Information for more details. [14C]-monosaccharide uptake inhibition experiments Materials and Methods In brief, 0.6 μCi [14C]-labelled monosaccharide was added to ◦ Chemicals stable cell lines pre-incubated at 37 C in 200 μluptakebuffer. Empagliflozin (BI 10773; 1-chloro-4-(β-D-glucopyranos-1- Cells were incubated for 60 min (hSGLT-5), 90 min (hSGLT-4) ◦ yl)-2-[4-((S)-tetrahydrofuran-3-yl-oxy)-benzyl]-benzene; or 4 h (hSGLT-2) at 37 C, then washed three times with figure 1) was synthesised at Boehringer Ingelheim Pharma phosphate-buffered saline (PBS) and lysed in 0.1 N NaOH. The GmbH & Co.KG, Biberach, Germany. Empagliflozin can be lysate was mixed with 200 μl MicroScint 40, shaken for 15 min synthesised as described in patent: WO 2005/092877 A1 or in and counted for radioactivity in the TopCount NXT (Canberra WO 2006/120208 A1. The crystalline form of empagliflozin Packard, Schwadorf, Austria). A dose-response curve was fitted is described in WO 2006/117359 A1. [3H]-empagliflozin (32 to an empirical four-parameter model using XL Fit (IDBS, Ci/mmol) was synthesised at Tritec (Teufen, Switzerland). Guildford, UK) to determine the inhibitor concentration at Dapagliflozin, canagliflozin, remogliflozin, sergliflozin and half-maximal response (IC50). See the Supporting Information T-1095A were synthesised at Boehringer Ingelheim Pharma for more details. GmbH & Co.KG, Biberach, Germany. Ipragliflozin was synthe- sised at Mercachem (Nijmegen, The Netherlands). Foetal calf HEK293-hSGLT-2 Membrane preparation serum was from Biological Industries (Kibbutz Beit-Haemek, At 90% confluency, cells were collected in cold PBS without ◦ Israel), Dulbecco’s Minimal Essential Medium from Cambrex Ca2+ and Mg2+ (4 C) and sonificated (Dr Hielscher GmbH, (East Rutherford, NJ, USA), Zeocin from Invitrogen (Carlsbad, UP 50H) for 3 × 30 s on ice; cell debris was removed by ◦ CA, USA), ethylene diamine tetraacetic acid, sodium chloride centrifugation at 33 × g for 5 min at 4 C and supernatants ◦ (NaCl) and sodium hydroxide (NaOH) from Merck (Darm- centrifuged at 18 000 × g for 60 min at 4 C. Supernatant was ◦ stadt, Germany) and alpha-D-glucose and polyethylenimine discarded and membrane pellet was stored at −80 C. Protein from Sigma (St. Louis, MO, USA). Packard Unifilter-96 GF/B content was determined using the BCA Protein Assay Reagent Filterplates, TopSeals, Microscint 20 and UltimaGold were Kit (Bio-Rad, CA, USA). obtained from Perkin Elmer (Waltham, MA, USA). Radioligand binding assays using [3H]-labelled Cell lines empagliflozin HEK293 cells (ATCC) were stably transfected with vec- Membranes (60 μg/well) were assayed in a 10 mM 4- tors for human (h) SGLT-1 (HEK293-hSGLT-1), hSGLT-2 (2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) 84 Grempler et al.
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