N-glucosides as human sodium-dependent glucose cotransporter 2 (hSGLT2) inhibitors

• Published in: Bioorganic & medicinal chemistry letters Vol. 23; no. 20; pp. 5641 - 5645
• Main Authors: Yamamoto, Yasuo, Kawanishi, Eiji, Koga, Yuichi, Sakamaki, Shigeki, Sakamoto, Toshiaki, Ueta, Kiichiro, Matsushita, Yasuaki, Kuriyama, Chiaki, Tsuda-Tsukimoto, Minoru, Nomura, Sumihiro
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.10.2013; Elsevier
• Subjects: Animals; Blood; blood glucose; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Diabetes; excretion; glucose; Glucose - metabolism; Glucoside; Glucosides - chemical synthesis; Glucosides - chemistry; Glucosides - pharmacokinetics; Half-Life; Humans; hyperglycemia; Indoles - chemical synthesis; Indoles - chemistry; Indoles - pharmacokinetics; Life Sciences & Biomedicine; N-glucoside; pharmacokinetics; Pharmacology & Pharmacy; Physical Sciences; Protein Binding; Rats; Science & Technology; SGLT2; Sodium-dependent glucose cotransporter; Sodium-Glucose Transporter 2 - antagonists & inhibitors; Sodium-Glucose Transporter 2 - metabolism; Structure-Activity Relationship; Diabetes; SGLT2; N-glucoside; Sodium-dependent glucose cotransporter; Glucoside; MECHANISM; SGLT2 INHIBITORS; DISCOVERY; DIABETES-MELLITUS; POTENT; RING; NA+/GLUCOSE COTRANSPORTER; TYPE-2; REABSORPTION
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2013.08.042

A series of N-glucosides was synthesized for biological evaluation as human hSGLT2 inhibitors. Compound 9d possessing an indole core structure showed good in vitro activity and favorable in vivo potency with regard to urinary glucose excretion (UGE) in rats. Inhibition of renal sodium-dependent glucose cotransporter 2 (SGLT2) increases urinary glucose excretion (UGE), and thus reduces blood glucose levels in hyperglycemia. A series of N-glucosides was synthesized for biological evaluation as human SGLT2 (hSGLT2) inhibitors. Among these compounds, N-glucoside 9d possessing an indole core structure showed good in vitro activity (IC50=7.1nM against hSGLT2). Furthermore, 9d exhibited favorable in vivo potency with regard to UGE in rats based on good pharmacokinetic profiles.