TS‐071 is a novel, potent and selective renal sodium‐glucose cotransporter 2 (SGLT2) inhibitor with anti‐hyperglycaemic activity

• Published in: British journal of pharmacology 2011-09, Vol.164 (1), p.181-191
• Main Authors: Yamamoto, K, Uchida, S, Kitano, K, Fukuhara, N, Okumura‐Kitajima, L, Gunji, E, Kozakai, A, Tomoike, H, Kojima, N, Asami, J, Toyoda, H, Arai, M, Takahashi, T, Takahashi, K
• Format: Article
• Language: English
• Subjects: Animals; anti‐diabetic agent; Biological and medical sciences; Blood Glucose - metabolism; CHO Cells; Cricetinae; Cricetulus; Deoxyglucose - metabolism; Diabetes Mellitus - drug therapy; Diabetes Mellitus - metabolism; Diabetes Mellitus, Experimental - drug therapy; Diabetes Mellitus, Experimental - metabolism; Diabetes. Impaired glucose tolerance; Dogs; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Glycosuria - drug therapy; Glycosuria - metabolism; Humans; Hyperglycemia - blood; Hyperglycemia - drug therapy; Hyperglycemia - metabolism; Hypoglycemic Agents - pharmacokinetics; Hypoglycemic Agents - pharmacology; Insulin - metabolism; Insulin Secretion; Kidney - drug effects; Kidney - metabolism; Male; Medical sciences; Mice; Mice, Inbred C57BL; Pharmacology. Drug treatments; Rats; Rats, Sprague-Dawley; Rats, Zucker; renal tubules; Research Papers; SGLT2 inhibitor; Sodium-Glucose Transporter 1 - metabolism; Sodium-Glucose Transporter 2 - metabolism; Sodium-Glucose Transporter 2 Inhibitors; sodium‐glucose cotransporter; Sorbitol - analogs & derivatives; Sorbitol - pharmacokinetics; Sorbitol - pharmacology; TS‐071; type 2 diabetes mellitus; urinary glucose excretion
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.2011.01340.x

BACKGROUND AND PURPOSE The renal sodium‐glucose cotransporter 2 (SGLT2) plays an important role in the reuptake of filtered glucose in the proximal tubule and therefore may be an attractive target for the treatment of diabetes mellitus. This study characterizes the pharmacological profile of TS‐071 ((1S)‐1,5‐anhydro‐1‐[5‐(4‐ethoxybenzyl)‐2‐methoxy‐4‐methylphenyl]‐1‐thio‐d‐glucitol hydrate), a novel SGLT2 inhibitor in vitro and in vivo. EXPERIMENTAL APPROACH Inhibition of glucose uptake by TS‐071 was studied in CHO‐K1 cells stably expressing either human SGLT1 or SGLT2. Single oral dosing studies were performed in rats, mice and dogs to assess the abilities of TS‐071 to increase urinary glucose excretion and to lower plasma glucose levels. KEY RESULTS TS‐071 inhibited SGLT2 activity in a concentration‐dependent manner and was a potent and highly selective inhibitor of SGLT2. Orally administered TS‐071 increased urinary glucose excretion in Zucker fatty rats and beagle dogs at doses of 0.3 and 0.03 mg·kg−1 respectively. TS‐071 improved glucose tolerance in Zucker fatty rats without stimulating insulin secretion and reduced hyperglycaemia in streptozotocin (STZ)‐induced diabetic rats and db/db mice at a dose of 0.3 mg·kg−1. CONCLUSION AND IMPLICATIONS These data indicate that TS‐071 is a potent and selective SGLT2 inhibitor that improves glucose levels in rodent models of type 1 and 2 diabetes and may be useful for the treatment for diabetes mellitus.