Discovery of Canagliflozin, a Novel C-Glucoside with Thiophene Ring, as Sodium-Dependent Glucose Cotransporter 2 Inhibitor for the Treatment of Type 2 Diabetes Mellitus

• Published in: Journal of medicinal chemistry Vol. 53; no. 17; pp. 6355 - 6360
• Main Authors: Nomura, Sumihiro, Sakamaki, Shigeki, Hongu, Mitsuya, Kawanishi, Eiji, Koga, Yuichi, Sakamoto, Toshiaki, Yamamoto, Yasuo, Ueta, Kiichiro, Kimata, Hirotaka, Nakayama, Keiko, Tsuda-Tsukimoto, Minoru
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 09.09.2010; Amer Chemical Soc
• Subjects: Animals; Biological Availability; Canagliflozin; Carbonates - pharmacology; Chemistry, Medicinal; Diabetes Mellitus, Type 2 - drug therapy; Glucosides - chemical synthesis; Glucosides - pharmacokinetics; Glucosides - pharmacology; Humans; Hypoglycemic Agents - chemical synthesis; Hypoglycemic Agents - pharmacokinetics; Hypoglycemic Agents - pharmacology; Life Sciences & Biomedicine; Male; Mice; Pharmacology & Pharmacy; Rats; Rats, Sprague-Dawley; Science & Technology; Sodium-Glucose Transporter 2 - antagonists & inhibitors; Stereoisomerism; Structure-Activity Relationship; Thiophenes - chemical synthesis; Thiophenes - pharmacokinetics; Thiophenes - pharmacology; ANTIDIABETIC AGENTS; PREVALENCE; REDUCTION; MECHANISM; SGLT2 INHIBITORS; DERIVATIVES

We discovered that C-glucosides 4 bearing a heteroaromatic ring formed metabolically more stable inhibitors for sodium-dependent glucose cotransporter 2 (SGLT2) than the O-glucoside, 2 (T-1095). A novel thiophene derivative 4b-3 (canagliflozin) was a highly potent and selective SGLT2 inhibitor and s...