Pharmacological Research 63 (2011) 284–293 Contents lists available at ScienceDirect Pharmacological Research j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / y p h r s EGT1442, a potent and selective SGLT2 inhibitor, attenuates blood glucose and HbA 1c levels in db/db mice and prolongs the survival of stroke-prone rats Wenbin Zhang a,b , Ajith Welihinda c,1 , Jordan Mechanic c,2 , Haifeng Ding b , Liangcheng Zhu b , Yuan Lu b , Zhongping Deng b , Zelin Sheng b , Binhua Lv b , Yuanwei Chen b , Jacques Y. Roberge b , Brian Seed b,c,∗∗ , Yong-Xiang Wang a,b,∗ a King’s Lab, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China b Egret Pharma Shanghai Ltd., Shanghai, China c Theracos, Inc., CA, USA a r t i c l e i n f o Article history: Received 26 November 2010 Received in revised form 29 December 2010 Accepted 2 January 2011 Keywords: EGT1442 SGLT2 inhibitor Diabetes db/db mice Urinary glucose excretion Stroke-prone rats a b s t r a c t Sodium glucose co-transporter 2 (SGLT2) is a renal type III integral membrane protein that co-transports sodium and glucose from filtrate to epithelium in the proximal tubule. Human subjects with homozy- gous or compound heterozygous mutations in SLC5A2 exhibit glucosuria without hypoglycemia or other obvious morbidity, suggesting that blockade of SGLT2 has the potential to promote normalization of blood glucose without hypoglycemia in the setting of type 2 diabetes. This report presents the in vitro and in vivo pharmacological activities of EGT1442, a recently discovered SGLT2 inhibitor in the C-aryl glucoside class. The inhibitory effects of EGT1442 for human SGLT1 and SGLT2 were evaluated in an AMG uptake assay and the in vivo efficacy of treatment with EGT1442 was investigated in rats and dogs after a single dose and in db/db mice after chronic administration. The effect of EGT1442 on median survival of SHRSP rats was also evaluated. The IC 50 values for EGT1442 against human SGLT1 and SGLT2 are 5.6 ␮M and 2 nM, respectively.In normal rats and dogs a saturable urinary glucose excretion was produced with an ED 50 of 0.38 and 0.09 mg/kg,respectively.Following chronic administration to db/db mice,EGT1442 dose-dependently reduced HbA 1c and blood glucose concentration without affecting body mass or insulin level. Additionally, EGT1442 significantly prolonged the median survival of SHRSP rats. EGT1442 showed favorable properties both in vitro and in vivo and could be beneficial to the manage- ment of type 2 diabetic patients. © 2011 Elsevier Ltd. All rights reserved. 1. Introduction Type 2 diabetes mellitus (T2DM) is a disease of grow- ing impact on developed and developing societies worldwide Abbreviations: SGLT, sodium glucose co-transporter; UGE, urinary glucose excretion; AUC,area under the curve; AMG,methyl-␣-glucopyranoside; PEG 400, polyethylene glycol-400; T2DM, type 2 diabetes; SHRSP, spontaneously hyperten- sive stroke prone rats. ∗ Corresponding author at: The No. 6 Biomedicine Building (Suite 106), 800 Dongchuan Road, Shanghai 200240, China. Tel.: +86 21 3420 4763; fax: +86 21 3420 4763. ∗∗ Corresponding author at: Theracos, Inc., 550 Del Rey Ave., Sunnyvale, CA 94085, USA. Tel.: +1 617 726 5975; fax: +1 617 643 3328. E-mail addresses: bseed@theracos.com (B. Seed), yxwang@sjtu.edu.cn (Y.-X. Wang). 1 Present address: Molecular Medicine Research Institute, CA, USA. 2 Present address: Trigemina, Inc., CA, USA. [1]. Recent data from the World Health Organization estimates the global prevalence at approximately 180 million individuals (http://www.who.int/mediacentre/factsheets/fs312/en/). Contem- porary treatment of T2DM emphasizes oral anti-diabetic agents, often in combination therapy, until adequate glycemic control can no longer be maintained, at which point insulin is typically added to the regimen. Although prescribing patterns vary geographically, the first line agents are typically biguanides (particularly met- formin), sulfonylureas, and alpha glucosidase inhibitors. Secondary agents include thiazolidinediones and DPP-4 inhibitors, and are often followed by insulin in various forms and GLP-1 analogs. Only 37% of T2DM patients are thought to achieve the recommended HbA 1c target of less than 7% [2]. Recently, therapeutic strategies to inhibit the renal sodium glu- cose co-transporter 2, SGLT2, have been developed and advanced to late phase clinical testing [3]. SGLT2 is a low affinity high capacity glucose transporter exclusively expressed in the S1 and S2 seg- ments of the renal proximal tubule [4] that mediates sodium and 1043-6618/$ – see front matter © 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.phrs.2011.01.001