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

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...

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Published inJournal 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
LanguageEnglish
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
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Summary: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 showed pronounced anti-hyperglycemic effects in high-fat diet fed KK (HF-KK) mice.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:0022-2623
1520-4804
DOI:10.1021/jm100332n