Research Laboratories, Kyoto Pharmaceutical Industries, Ltd, 38, Nishinokyo Tsukinowa-cho, Nakagyo-ku, Kyoto 604-8444, Japan.
Bioorg Med Chem. 2012 Jan 15;20(2):1060-75. doi: 10.1016/j.bmc.2011.11.035. Epub 2011 Dec 1.
A novel series of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives were synthesized and (S)-2-[(2E,4E)-hexadienoyl]-7-(2-{5-methyl-2-[(1E)-5-methylhexen-1-yl]oxazol-4-yl}ethoxy)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (14i) was identified as a potent human peroxisome proliferator-activated receptor γ (PPARγ) selective agonist (EC(50)=0.03 μM) and human protein-tyrosine phosphatase 1B (PTP-1B) inhibitor (IC(50)=1.18 μM). C(max) after oral administration of 14i at 10mg/kg was 2.2 μg/ml (4.5 μM) in male SD rats. Repeated administration of 14i and rosiglitazone for 14 days dose-dependently decreased plasma glucose levels, ED(50)=4.3 and 23 mg/kg/day, respectively, in male KK-A(y) mice. In female SD rats, repeated administration of 14i at 12.5-100mg/kg/day for 28 days had no effect on the hematocrit value (Ht) and red blood cell count (RBC), while rosiglitazone significantly decreased them from 25mg/kg/day. In conclusion, 14i showed about a fivefold stronger hypoglycemic effect and fourfold or more weaker hemodilution effect than rosiglitazone, indicating that 14i is 20-fold or more safer than rosiglitazone. Compound 14i is a promising candidate for an efficacious and safe anti-diabetic drug targeting PPARγ and PTP-1B.
合成了一系列新型 1,2,3,4-四氢异喹啉-3-羧酸衍生物，其中（S）-2-[(2E,4E)-己二烯酰基]-7-(2-{5-甲基-2-[(1E)-5-甲基-1-己烯基]恶唑-4-基}乙氧基)-1,2,3,4-四氢异喹啉-3-羧酸（14i）被鉴定为一种有效的人过氧化物酶体增殖物激活受体γ（PPARγ）选择性激动剂（EC50=0.03 μM）和人蛋白酪氨酸磷酸酶 1B（PTP-1B）抑制剂（IC50=1.18 μM）。雄性 SD 大鼠口服 14i 10mg/kg 后，Cmax 为 2.2μg/ml（4.5 μM）。连续给予 14i 和罗格列酮 14 天，剂量依赖性地降低雄性 KK-A（y）小鼠的血浆葡萄糖水平，ED50 分别为 4.3 和 23mg/kg/天。在雌性 SD 大鼠中，连续给予 14i 12.5-100mg/kg/天 28 天对红细胞压积（Ht）和红细胞计数（RBC）没有影响，而罗格列酮则使 RBC 从 25mg/kg/天开始显著降低。总之，14i 的降血糖作用比罗格列酮强约五倍，血液稀释作用比罗格列酮弱四倍或更多，表明 14i 的安全性比罗格列酮高 20 倍以上。化合物 14i 是一种有前途的候选药物，可作为针对 PPARγ 和 PTP-1B 的有效和安全的抗糖尿病药物。
