title: Novel Indole-N-glucoside, TA-1887 As a Sodium Glucose Cotransporter 2 Inhibitor for Treatment of Type 2 Diabetes.
abstract: Inhibition of the renal sodium glucose cotransporter (SGLT) increases urinary glucose excretion (UGE) and thus reduces blood glucose levels during hyperglycemia. To explore the potential of new antihyperglycemic agents, we synthesized and determined the human SGLT2 (hSGLT2) inhibitory potential of novel substituted 3-benzylindole-N-glucosides 6. Optimization of 6 resulted in the discovery of 3-(4-cyclopropylbenzyl)-4-fluoroindole-N-glucoside 6a-4 (TA-1887), a highly potent and selective hSGLT2 inhibitor, with pronounced antihyperglycemic effects in high-fat diet-fed KK (HF-KK) mice. Our results suggest the potential of indole-N-glucosides as novel antihyperglycemic agents through inhibition of renal SGLT2.
authors.affiliation: Medicinal Chemistry Research Laboratories, Pharmacology Research Laboratories, and DMPK Research Laboratories, Mitsubishi Tanabe Pharma Corporation , 2-2-50 Kawagishi, Toda, Saitama 335-8505, Japan.
authors.forename: Sumihiro
authors.initials: S
authors.lastname: Nomura
authors.affiliation: Medicinal Chemistry Research Laboratories, Pharmacology Research Laboratories, and DMPK Research Laboratories, Mitsubishi Tanabe Pharma Corporation , 2-2-50 Kawagishi, Toda, Saitama 335-8505, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Yamamoto
authors.affiliation: Medicinal Chemistry Research Laboratories, Pharmacology Research Laboratories, and DMPK Research Laboratories, Mitsubishi Tanabe Pharma Corporation , 2-2-50 Kawagishi, Toda, Saitama 335-8505, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Matsumura
authors.affiliation: Medicinal Chemistry Research Laboratories, Pharmacology Research Laboratories, and DMPK Research Laboratories, Mitsubishi Tanabe Pharma Corporation , 2-2-50 Kawagishi, Toda, Saitama 335-8505, Japan.
authors.forename: Kiyomi
authors.initials: K
authors.lastname: Ohba
authors.affiliation: Medicinal Chemistry Research Laboratories, Pharmacology Research Laboratories, and DMPK Research Laboratories, Mitsubishi Tanabe Pharma Corporation , 2-2-50 Kawagishi, Toda, Saitama 335-8505, Japan.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Sakamaki
authors.affiliation: Medicinal Chemistry Research Laboratories, Pharmacology Research Laboratories, and DMPK Research Laboratories, Mitsubishi Tanabe Pharma Corporation , 2-2-50 Kawagishi, Toda, Saitama 335-8505, Japan.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Kimata
authors.affiliation: Medicinal Chemistry Research Laboratories, Pharmacology Research Laboratories, and DMPK Research Laboratories, Mitsubishi Tanabe Pharma Corporation , 2-2-50 Kawagishi, Toda, Saitama 335-8505, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Nakayama
authors.affiliation: Medicinal Chemistry Research Laboratories, Pharmacology Research Laboratories, and DMPK Research Laboratories, Mitsubishi Tanabe Pharma Corporation , 2-2-50 Kawagishi, Toda, Saitama 335-8505, Japan.
authors.forename: Chiaki
authors.initials: C
authors.lastname: Kuriyama
authors.affiliation: Medicinal Chemistry Research Laboratories, Pharmacology Research Laboratories, and DMPK Research Laboratories, Mitsubishi Tanabe Pharma Corporation , 2-2-50 Kawagishi, Toda, Saitama 335-8505, Japan.
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Matsushita
authors.affiliation: Medicinal Chemistry Research Laboratories, Pharmacology Research Laboratories, and DMPK Research Laboratories, Mitsubishi Tanabe Pharma Corporation , 2-2-50 Kawagishi, Toda, Saitama 335-8505, Japan.
authors.forename: Kiichiro
authors.initials: K
authors.lastname: Ueta
authors.affiliation: Medicinal Chemistry Research Laboratories, Pharmacology Research Laboratories, and DMPK Research Laboratories, Mitsubishi Tanabe Pharma Corporation , 2-2-50 Kawagishi, Toda, Saitama 335-8505, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Tsuda-Tsukimoto
keywords: TA-1887; Type 2 diabetes; antihyperglycemic effect; indole-N-glucoside; sodium glucose cotransporter 2 inhibitor; urinary glucose excretion