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

  • Bioorg Med Chem. 2013 Jul 1;21(13):3934-48. doi: 10.1016/j.bmc.2013.03.067.
Kazuhiro Ikegai  1 ,  Masakazu Imamura ,  Takayuki Suzuki ,  Keita Nakanishi ,  Takeshi Murakami ,  Eiji Kurosaki ,  Atsushi Noda ,  Yoshinori Kobayashi ,  Masayuki Yokota ,  Tomokazu Koide ,  Kazuhiro Kosakai ,  Yasufumi Ohkura ,  Makoto Takeuchi ,  Hiroshi Tomiyama ,  Mitsuaki Ohta
Affiliations
  • 1. Drug Discovery Research, Astellas Pharmaceutical Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. [email protected]
PMID: 23651509 DOI: 10.1016/j.bmc.2013.03.067
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.

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