6 -Benzylphenyl-2 - sulfurterahydropyran-3, 4, 5 -triol derivatives as inhibitors of sodium -glucose cotrans porters 1 and 2 for use in diabetic patients

A dual inhibitor, patient technology, which can be used in medical preparations containing active ingredients, metabolic diseases, drug combinations, etc., and can solve the problems of glucose-galactose absorption disorder, high urinary sugar excretion, etc.

Inactive Publication Date: 2012-12-12
LEXICON PHARM INC
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Problems solved by technology

This is apparently based, at least in part, on the fact that, while individuals lacking a functional SGLT2 gene appear to be able to lead normal lives in addition to exhibiting high urinary glucose excretion, individuals with mutations in the SGLT1 gene experience glucose-galactose Malabsorption

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  • 6 -Benzylphenyl-2 - sulfurterahydropyran-3, 4, 5 -triol derivatives as inhibitors of sodium -glucose cotrans porters 1 and 2 for use in diabetic patients
  • 6 -Benzylphenyl-2 - sulfurterahydropyran-3, 4, 5 -triol derivatives as inhibitors of sodium -glucose cotrans porters 1 and 2 for use in diabetic patients
  • 6 -Benzylphenyl-2 - sulfurterahydropyran-3, 4, 5 -triol derivatives as inhibitors of sodium -glucose cotrans porters 1 and 2 for use in diabetic patients

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Embodiment Construction

[0258] In vitro human SGLT2 inhibition assay

[0259] Human sodium / glucose cotransporter type 2 (SGLT2; accession number P31639; GI:400337) was cloned in the pIRESpuro2 vector for mammalian expression (construct: HA-SGLT2-pIRESpuro2).

[0260] HEK293 cells were transfected with the human HA-SGLT2-pIRESpuro2 vector, and the main stable cell line was selected in the presence of 0.5 μg / ml puromycin. Human HA-SGLT2 cells were maintained in DMEM medium containing 10% FBS, 1% GPS and 0.5 μg / ml puromycin.

[0261] HEK293 cells expressing human HA-SGLT2 were seeded in 384-well plates (30,000 cells / well) in DMEM medium containing 10% FBS, 1% GPS, and 0.5 μg / ml puromycin, and then incubated at 37 °C and 5 %CO 2 Incubate overnight. Cells were then washed with uptake buffer (140 mM NaCl, 2 mM KCl, 1 mM CaCl 2 , 1 mM MgCl 2 , 10mM HEPES, 5mM Tris, 1mg / ml bovine serum albumin (BSA), pH 7.3) for washing. 20 microliters of uptake buffer with or without test compound was added to the c...

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Abstract

Methods of improving the cardiovascular and / or metabolic health of patients, particularly those suffering from type 2 diabetes, are disclosed, as well as compounds and pharmaceutical compositions useful therein.

Description

technical field [0001] The present invention relates to methods of improving the cardiovascular and / or metabolic health of patients, particularly patients with type 2 diabetes, and compounds and pharmaceutical compositions useful therein. Background technique [0002] Type 2 diabetes mellitus (T2DM) is a disorder characterized by elevated serum glucose. One way to lower serum glucose in patients with this disease is to inhibit glucose reabsorption in the kidneys. The kidneys play an important role in the overall control of glucose, as glucose is filtered out through the glomerulus at a rate of approximately 8 g / h and is almost completely reabsorbed in the proximal tubule by the sodium–glucose cotransporter (SGLT). Komoroski, B. et al., Clin Pharmacol Ther. 85(5):513-9 (2009). Sodium-glucose cotransporter 2 (SGLT2) is a 14-transmembrane domain SGLT and is responsible for the reabsorption of most glucose filtered out at the glomerulus. Therefore, inhibition of SGLT2 is a r...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/351A61P9/00
CPCA61K31/7028A61K31/351A61K31/4985A61K31/155A61K45/06A61P3/00A61P3/04A61P3/06A61P43/00A61P9/00A61P9/12A61P3/10A61K2300/00C07D309/32
Inventor 菲利普·曼顿·布朗乔尔·菲利普·弗雷曼戴维·里德·伯维尔
Owner LEXICON PHARM INC
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