title: TS-071 is a novel, potent and selective renal sodium-glucose cotransporter 2 (SGLT2) inhibitor with anti-hyperglycaemic activity.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Molecular Function and Pharmacology Laboratories, Taisho Pharmaceutical Co., Ltd, Saitama, Japan. koji.yamamoto@po.rd.taisho.co.jp
authors.forename: K
authors.initials: K
authors.lastname: Yamamoto
authors.forename: S
authors.initials: S
authors.lastname: Uchida
authors.forename: K
authors.initials: K
authors.lastname: Kitano
authors.forename: N
authors.initials: N
authors.lastname: Fukuhara
authors.forename: L
authors.initials: L
authors.lastname: Okumura-Kitajima
authors.forename: E
authors.initials: E
authors.lastname: Gunji
authors.forename: A
authors.initials: A
authors.lastname: Kozakai
authors.forename: H
authors.initials: H
authors.lastname: Tomoike
authors.forename: N
authors.initials: N
authors.lastname: Kojima
authors.forename: J
authors.initials: J
authors.lastname: Asami
authors.forename: H
authors.initials: H
authors.lastname: Toyoda
authors.forename: M
authors.initials: M
authors.lastname: Arai
authors.forename: T
authors.initials: T
authors.lastname: Takahashi
authors.forename: K
authors.initials: K
authors.lastname: Takahashi
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D003847:Deoxyglucose / Q000378:metabolism; D003920:Diabetes Mellitus / Q000188:drug therapy / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism; D004285:Dogs; D006029:Glycosuria / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D006943:Hyperglycemia / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker; D051269:Sodium-Glucose Transporter 1 / Q000378:metabolism; D051297:Sodium-Glucose Transporter 2 / Q000378:metabolism; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013012:Sorbitol / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; C495674:SLC5A1 protein, human; C089180:SLC5A2 protein, human; D051269:Sodium-Glucose Transporter 1; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013012:Sorbitol; D003847:Deoxyglucose; C549343:1,5-anhydro-1-(5-(4-ethoxybenzyl)-2-methoxy-4-methylphenyl)-1-thioglucitol