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  3. 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

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

Affiliation

  • 1 Drug Discovery Research, Astellas Pharmaceutical Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. kazuhiro.ikegai@astellas.com
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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