Minoura Hideaki, Takeshita Shigeru, Ita Makoto, Hirosumi Jiro, Mabuchi Miyuki, Kawamura Ikuo, Nakajima Satoko, Nakayama Osamu, Kayakiri Hiroshi, Oku Teruo, Ohkubo-Suzuki Akiko, Fukagawa Masao, Kojo Hitoshi, Hanioka Kenichi, Yamasaki Noritsugu, Imoto Takafumi, Kobayashi Yoshinori, Mutoh Seitaro
Research Division, Fujisawa Pharmaceutical Co., Ltd., 2-1-6, Kashima, Yodogawa, Osaka 532-8514, Japan.
Eur J Pharmacol. 2004 Jun 28;494(2-3):273-81. doi: 10.1016/j.ejphar.2004.04.038.
We evaluated antidiabetic effects of 3-(2,4-dichlorobenzyl)-2-methyl-N-(pentylsulfonyl)-3 H-benzimidazole-5-carboxamide (FK614), a benzimidazole derivative without a thiazolidinedione structure, which was obtained using C57BL/KsJ-db/db mice (db/db mice). In db/db mice, the potency of FK614 for hypoglycemic effect was comparable to that of rosiglitazone and approximately 15-fold greater than that of pioglitazone. FK614 also showed a potent attenuating effect on hypertriglyceridemia in db/db mice, as well as rosiglitazone and pioglitazone. In C57BL/6J-ob/ob mice (ob/ob mice), ED(50) values of FK614 and pioglitazone for hypoinsulinemic effect were 1.3 and 11.8 mg/kg, respectively. FK614 also improved the impaired glucose tolerance in ob/ob mice. In normal rats, FK614 did not influence plasma glucose and insulin levels but significantly decreased both plasma triglyceride and nonesterified fatty acid levels. FK614 was found to activate peroxisome proliferator-activated receptor (PPAR)gamma-mediated transcriptional activity in the reporter gene assay as well as thiazolidinedione derivatives, although its maximum effect was less than that of thiazolidinedione derivatives. In rat toxicity studies, hemodilution effects for FK614 were less than that for rosiglitazone. Overall, these studies suggest that FK614 improves insulin resistance in such animal models through activation of PPARgamma-mediated transcriptional activity and that it would be a new therapeutic candidate with potential for the treatment of type 2 diabetic patients.
我们评估了3-(2,4-二氯苄基)-2-甲基-N-(戊基磺酰基)-3H-苯并咪唑-5-甲酰胺（FK614）的抗糖尿病作用，FK614是一种不含噻唑烷二酮结构的苯并咪唑衍生物，使用C57BL/KsJ-db/db小鼠（db/db小鼠）获得。在db/db小鼠中，FK614的降血糖效力与罗格列酮相当，比吡格列酮大约强15倍。FK614对db/db小鼠的高甘油三酯血症也显示出强效的减轻作用，与罗格列酮和吡格列酮一样。在C57BL/6J-ob/ob小鼠（ob/ob小鼠）中，FK614和吡格列酮降低胰岛素水平的半数有效剂量（ED50）分别为1.3和11.8mg/kg。FK614还改善了ob/ob小鼠受损的糖耐量。在正常大鼠中，FK614不影响血浆葡萄糖和胰岛素水平，但显著降低血浆甘油三酯和非酯化脂肪酸水平。在报告基因测定中发现，FK614与噻唑烷二酮衍生物一样能激活过氧化物酶体增殖物激活受体（PPAR）γ介导的转录活性，尽管其最大效应小于噻唑烷二酮衍生物。在大鼠毒性研究中，FK614的血液稀释作用小于罗格列酮。总体而言，这些研究表明，FK614通过激活PPARγ介导的转录活性改善此类动物模型中的胰岛素抵抗，它可能是治疗2型糖尿病患者的一种新的潜在治疗候选药物。
