JOURNAL ARTICLE

(1S)-1,5-anhydro-1-[5-(4-ethoxybenzyl)-2-methoxy-4-methylphenyl]-1-thio-D-glucitol (TS-071) is a potent, selective sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor for type 2 diabetes treatment

Hiroyuki Kakinuma, Takahiro Oi, Yuko Hashimoto-Tsuchiya, Masayuki Arai, Yasunori Kawakita, Yoshiki Fukasawa, Izumi Iida, Naoko Hagima, Hiroyuki Takeuchi, Yukihiro Chino, Jun Asami, Lisa Okumura-Kitajima, Fusayo Io, Daisuke Yamamoto, Noriyuki Miyata, Teisuke Takahashi, Saeko Uchida, Koji Yamamoto
Journal of Medicinal Chemistry 2010 April 22, 53 (8): 3247-61
20302302
Derivatives of a novel scaffold, C-phenyl 1-thio-D-glucitol, were prepared and evaluated for sodium-dependent glucose cotransporter (SGLT) 2 and SGLT1 inhibition activities. Optimization of substituents on the aromatic rings afforded five compounds with potent and selective SGLT2 inhibition activities. The compounds were evaluated for in vitro human metabolic stability, human serum protein binding (SPB), and Caco-2 permeability. Of them, (1S)-1,5-anhydro-1-[5-(4-ethoxybenzyl)-2-methoxy-4-methylphenyl]-1-thio-D-glucitol (3p) exhibited potent SGLT2 inhibition activity (IC(50) = 2.26 nM), with 1650-fold selectivity over SGLT1. Compound 3p showed good metabolic stability toward cryo-preserved human hepatic clearance, lower SPB, and moderate Caco-2 permeability. Since 3p should have acceptable human pharmacokinetics (PK) properties, it could be a clinical candidate for treating type 2 diabetes. We observed that compound 3p exhibits a blood glucose lowering effect, excellent urinary glucose excretion properties, and promising PK profiles in animals. Phase II clinical trials of 3p (TS-071) are currently ongoing.

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