Synthesis and biological evaluation of benzocyclobutane-C-glycosides as potent and orally active SGLT1/SGLT2 dual inhibitors

  • Bioorg Med Chem Lett. 2018 Apr 15;28(7):1182-1187. doi: 10.1016/j.bmcl.2018.02.057.
Gee-Hong Kuo  1 ,  Micheal D Gaul  2 ,  Yin Liang  2 ,  June Z Xu  2 ,  Fuyong Du  2 ,  Pamela Hornby  2 ,  Guozhang Xu  2 ,  Jenson Qi  2 ,  Nathaniel Wallace  2 ,  Seunghun Lee  2 ,  Eugene Grant  2 ,  William V Murray  2 ,  Keith Demarest  2
Affiliations
  • 1. Cardiovascular and Metabolism Research, Janssen Research and Development, L.L.C., Welsh & McKean Roads, Spring House, PA 19477, USA. Electronic address: [email protected].
  • 2. Cardiovascular and Metabolism Research, Janssen Research and Development, L.L.C., Welsh & McKean Roads, Spring House, PA 19477, USA.
PMID: 29523385 DOI: 10.1016/j.bmcl.2018.02.057
Abstract

Synthesis and biological evaluation of benzocyclobutane-C-glycosides as potent and orally active SGLT1/SGLT2 dual inhibitors are described. Compound 19 showed high inhibitory potency at SGLT1 (IC50 = 45 nM), and excellent potency at SGLT2 (IC50 = 1 nM). It also displayed excellent PK profiles in mice, rats, dogs and monkeys (F = 78-107%). In SD rats, compound 19 treatments significantly reduced blood glucose levels in a dose-dependent manner. In ZDF rats, compound 19 displayed anti-hyperglycemic effect up to 24 h. Therefore, compound 19 may serve as valuable pharmacological tool, and potential use as a treatment for metabolic syndrome.

Keywords
Anti-hyperglycemic effect; Benzocyclobutane-C-glycosides; SGLT1/2 dual inhibitor.
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