title: Pharmacological profile of ipragliflozin (ASP1941), a novel selective SGLT2 inhibitor, in vitro and in vivo.
abstract: The pharmacological profile of ipragliflozin (ASP1941; (1S)-1,5-anhydro-1-C-{3-[(1-benzothiophen-2-yl)methyl]-4-fluorophenyl}-D: -glucitol compound with L: -proline (1:1)), a novel SGLT2 selective inhibitor, was investigated. In vitro, the potency of ipragliflozin to inhibit SGLT2 and SGLT1 and stability were assessed. In vivo, the pharmacokinetic and pharmacologic profiles of ipragliflozin were investigated in normal mice, streptozotocin-induced type 1 diabetic rats, and KK-A(y) type 2 diabetic mice. Ipragliflozin potently and selectively inhibited human, rat, and mouse SGLT2 at nanomolar ranges and exhibited stability against intestinal glucosidases. Ipragliflozin showed good pharmacokinetic properties following oral dosing, and dose-dependently increased urinary glucose excretion, which lasted for over 12 h in normal mice. Single administration of ipragliflozin resulted in dose-dependent and sustained antihyperglycemic effects in both diabetic models. In addition, once-daily ipragliflozin treatment over 4 weeks improved hyperglycemia with a concomitant increase in urinary glucose excretion in both diabetic models. In contrast, ipragliflozin at pharmacological doses did not affect normoglycemia, as was the case with glibenclamide, and did not influence intestinal glucose absorption and electrolyte balance. These results suggest that ipragliflozin is an orally active SGLT2 selective inhibitor that induces sustained increases in urinary glucose excretion by inhibiting renal glucose reabsorption, with subsequent antihyperglycemic effect and a low risk of hypoglycemia. Ipragliflozin has, therefore, the therapeutic potential to treat hyperglycemia in diabetes by increasing glucose excretion into urine.
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki, 305-8585, Japan. atsuo.tahara@jp.astellas.com
authors.forename: Atsuo
authors.initials: A
authors.lastname: Tahara
authors.forename: Eiji
authors.initials: E
authors.lastname: Kurosaki
authors.forename: Masanori
authors.initials: M
authors.lastname: Yokono
authors.forename: Daisuke
authors.initials: D
authors.lastname: Yamajuku
authors.forename: Rumi
authors.initials: R
authors.lastname: Kihara
authors.forename: Yuka
authors.initials: Y
authors.lastname: Hayashizaki
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Takasu
authors.forename: Masakazu
authors.initials: M
authors.lastname: Imamura
authors.forename: Li
authors.initials: L
authors.lastname: Qun
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tomiyama
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Kobayashi
authors.forename: Atsushi
authors.initials: A
authors.lastname: Noda
authors.forename: Masao
authors.initials: M
authors.lastname: Sasamata
authors.forename: Masayuki
authors.initials: M
authors.lastname: Shibasaki
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D016466:CHO Cells; D050260:Carbohydrate Metabolism / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy / Q000652:urine; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000188:drug therapy* / Q000652:urine; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000652:urine; D041981:Gastrointestinal Tract / Q000187:drug effects / Q000378:metabolism; D005960:Glucosides / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D007004:Hypoglycemic Agents / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D007328:Insulin / Q000097:blood; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010695:Phlorhizin / Q000097:blood / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D051269:Sodium-Glucose Transporter 1 / Q000037:antagonists & inhibitors; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013876:Thiophenes / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D001786:Blood Glucose; D005960:Glucosides; D007004:Hypoglycemic Agents; D007328:Insulin; D051269:Sodium-Glucose Transporter 1; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013876:Thiophenes; C572941:ipragliflozin; D010695:Phlorhizin