2. Academic Validation
  3. Synthesis and biological evaluation of benzocyclobutane-C-glycosides as potent and orally active SGLT1/SGLT2 dual inhibitors

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

Affiliations

  • 1 Cardiovascular and Metabolism Research, Janssen Research and Development, L.L.C., Welsh & McKean Roads, Spring House, PA 19477, USA. Electronic address: gkuo@its.jnj.com.
  • 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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