MedicinalChemistry Laboratories, Taisho Pharmaceutical Co., Ltd. 1-403 Yoshino-cho, Kita-ku, Saitama-shi, Saitama 331-9530, Japan.
J Med Chem. 2010 Apr 22;53(8):3247-61. doi: 10.1021/jm901893x.
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.
新型支架 C-苯 1-硫代-D-葡萄糖醇的衍生物被制备并评价其对钠依赖性葡萄糖共转运蛋白（SGLT）2 和 SGLT1 的抑制活性。对芳环上取代基的优化得到了五个具有强抑制活性和选择性的 SGLT2 抑制剂。这些化合物的体外人代谢稳定性、人血清蛋白结合（SPB）和 Caco-2 通透性进行了评价。其中，（1S）-1,5-脱水-1-[5-（4-乙氧基苄基）-2-甲氧基-4-甲基苯基]-1-硫代-D-葡萄糖醇（3p）表现出强的 SGLT2 抑制活性（IC50 = 2.26 nM），对 SGLT1 的选择性为 1650 倍。化合物 3p 对冷冻保存的人肝清除具有良好的代谢稳定性、较低的 SPB 和中等的 Caco-2 通透性。由于 3p 可能具有可接受的人体药代动力学（PK）特性，它可能成为治疗 2 型糖尿病的临床候选药物。我们观察到化合物 3p 在动物体内表现出降低血糖、良好的尿糖排泄特性和有前景的 PK 特征。3p（TS-071）的 II 期临床试验目前正在进行中。
