title: Synthesis and biological evaluation of C-glucosides with azulene rings as selective SGLT2 inhibitors for the treatment of type 2 diabetes mellitus: discovery of YM543.
abstract: Here, a series of C-glucosides with azulene rings in the aglycon moiety was synthesized and the inhibitory activities toward hSGLT1 and hSGLT2 were evaluated. Starting from the azulene derivative 7 which had relatively good SGLT2 inhibitory activity, compound 8a which has a 3-[(azulen-2-yl)methyl]phenyl group was identified as a lead compound for further optimization. Introduction of a phenolic hydroxyl group onto the central benzene ring afforded a potent and selective SGLT2 inhibitor 8e, which reduced blood glucose levels in a dose-dependent manner in rodent diabetic models. A mono choline salt of 8e (YM543) was selected as a clinical candidate for use in treating type 2 diabetes mellitus.
authors: Drug Discovery Research, Astellas Pharmaceutical Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. kazuhiro.ikegai@astellas.com
authors: Kazuhiro
authors: K
authors: Ikegai
authors: Masakazu
authors: M
authors: Imamura
authors: Takayuki
authors: T
authors: Suzuki
authors: Keita
authors: K
authors: Nakanishi
authors: Takeshi
authors: T
authors: Murakami
authors: Eiji
authors: E
authors: Kurosaki
authors: Atsushi
authors: A
authors: Noda
authors: Yoshinori
authors: Y
authors: Kobayashi
authors: Masayuki
authors: M
authors: Yokota
authors: Tomokazu
authors: T
authors: Koide
authors: Kazuhiro
authors: K
authors: Kosakai
authors: Yasufumi
authors: Y
authors: Ohkura
authors: Makoto
authors: M
authors: Takeuchi
authors: Hiroshi
authors: H
authors: Tomiyama
authors: Mitsuaki
authors: M
authors: Ohta
mesh_terms: D000818:Animals; D052176:Azulenes / Q000737:chemistry / Q000627:therapeutic use; D001786:Blood Glucose / Q000032:analysis; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D005960:Glucosides / Q000737:chemistry* / Q000627:therapeutic use*; D007004:Hypoglycemic Agents / Q000737:chemistry* / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley; D051297:Sodium-Glucose Transporter 2 / Q000378:metabolism; D000077203:Sodium-Glucose Transporter 2 Inhibitors
chemical_list: D052176:Azulenes; D001786:Blood Glucose; D005960:Glucosides; D007004:Hypoglycemic Agents; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; C005525:azulene