3-Oxodapagliflozin as a potent and highly selective SGLT2 inhibitor for the treatment of type 2 diabetes

Abstract

Structural modifications of 3-OH in the glucose moiety of dapagliflozin(1), an approved potent sodium-dependent glucose transporter 2(SGLT2) inhibitor, led to 3-oxodapagliflozin(16), a highly potent and more selective SGLT2 inhibitor[IC₅₀(hSGLT1)/IC₅₀(hSGLT2)=2851 for compound 16 vs. 843 for compound 1]. 3-Oxodapagliflozin(16) exhibited in vitro(IC₅₀=1.0 nmol/L against hSGLT2 for compound 16 vs. 1.3 nmol/L for compound 1) and in vivo activities comparable to those of dapagliflozin(1). The bioactivities of 3-oxodapagliflozin (16) warrant its further evaluation as a promising SGLT2 inhibitor for the treatment of type 2 diabetes.

Keywords

SGLT2 inhibitor / Structure-activity relationship / Dapagliflozin

References

[1] Fowler M J. Clin. Diabetes, 2008, 26(2): 77.

[2] Hardman T C, Dubrey S W. Diabetes Ther., 2011, 2(3): 133.

[3] Washburn W N. J. Med. Chem., 2009, 52(7): 1785.

[4] Wright E M, Loo D D, Hirayama B A. Physiol. Rev., 2011, 91(2): 733.

[5] Meng M, Ellsworth B A, Nirschl A A, McCann P J, Patel M, Girotra R N, Wu G, Sher P M, Morrison E P, Biller S A, Zahler R, Deshpande P P, Pullockaran A, Hagan D L, Morgan N, Taylor J R, Obermeier M T, Humphreys W G, Khanna A, Discenza L, Robertson J M, Wang A, Han S, Wetterau J R, Janovitz E B, Flint O P, Whaley J M, Washburn W N. J. Med. Chem., 2008, 51(5): 1145.

[6] Nomura S, Sakamaki S, Hongu M, Kawanishi E, Koga Y, Sakamoto T, Yamamoto Y, Ueta K, Kimata H, Nakayama K, Tsuda-Tsukimoto M. J. Med. Chem., 2010, 53(17): 6355.

[7] Zhang L, Wang Y, Xu H, Shi Y, Liu B, Wei Q, Xu W, Tang L, Wang J, Zhao G. Med. Chem., 2014, 10(3): 304.

[8] Xu Q H, Li J Z, He J H, Zhao X, Huo Q S. Chem. Res. Chinese Universities, 2013, 29(4): 695.

[9] Zhang S, Wang Y L, Wei Q C, Xu W R, Tang L D, Zhao G L, Wang J W. Chin. Chem. Lett., 2013, 24(5): 429.

[10] Green J E, Bender D M, Jackson S, O’Donnell M J, McCarthy J R. Org. Lett., 2009, 11(4): 807.

[11] Horito S, Asano K, Umemura K, Hashimoto H, Yoshimura J. Carbohydr. Res., 1983, 121: 175.

[12] Yao H W, Cui C, Li Y Q, Wang L Z, Li Z M, Zhao W G. Chem. J. Chinese Universities, 2012, 33(7): 1481.

[13] Crich D, Hu T, Cai F. J. Org. Chem., 2008, 73(22): 8942.