Pill J, Kühnle H F
Therapeutics Research, Boehringer Mannheim, Germany.
Metabolism. 1999 Jan;48(1):34-40. doi: 10.1016/s0026-0495(99)90007-0.
BM 17.0744 (2,2-dichloro-12-(p-chlorophenyl)-dodecanoic acid) is a substance from a group of omega-substituted alkyl carboxylic acids with the general formula, ring-spacer-carboxylic acid. With BM 17.0744-a compound structurally unrelated to thiazolidinediones--antihyperglycemic and antihyperinsulinemic potency has been demonstrated in various animal models of type II diabetes. The antidiabetic effect is independent of the genetic background of the disease, gender, and animal species. The 24-hour blood glucose profile was dose- and time-dependently improved in ob/ob mice after a single and fourth oral administration of 0.3, 1, and 3 mg/kg/d. A dose-dependent reduction of hyperglycemia (10%, 15%, 28%, and 66%) was found in db/db mice after the fifth oral administration of 3, 10, 30, and 100 mg/kg/d. Hyperinsulinemia was reduced dose-dependently in yellow KK mice by 1%, 24%, 34%, and 66% after the fifth oral administration of 0.3, 1, 3, and 10 mg/kg/d. Overall glucose metabolism was predominantly higher in euglycemic-hyperinsulinemic clamp studies in obese fa/fa rats pretreated for 14 days with 10 mg/kg/d BM 17.0744. The data in diabetic and insulin-resistant animals suggest an improvement of insulin action that is supported by enhancement of insulin effects in vitro. There is no evidence of a risk for hypoglycemia in diabetic and metabolically healthy animals. Triglyceride (TG) and cholesterol were reduced in the serum of metabolically healthy rats, as well as serum lipids in db/db mice, which suggests this effect is independent of amelioration of the diabetic status. Lipid-lowering effects in diabetic and healthy animals show an additional property of BM 17.0744. Because of its antidiabetic and lipid-lowering potency, the substance is of great interest in treating the metabolic syndrome. Lipid decreases in rats are associated with a dose-dependent increase in carnitine acetyltransferase activity in the liver to about 100-fold (12.5 mg/kg/d). This together with hepatomegaly in small rodents may indicate peroxisomal proliferation, a phenomenon considered species-specific. Its relevance for humans is well documented for other classes of compounds including fibrates. Specific side effects of insulin sensitizers of the thiazolidinedione type, such as an increase in body weight and heart weight, could not be observed after 4-week oral application of BM 17.0744 in rats. In general, BM 17.0744 was well tolerated in the pharmacological dose range in all species tested.
BM 17.0744（2,2 - 二氯 - 12 -（对氯苯基）- 十二烷酸）是ω - 取代烷基羧酸类中的一种物质，其通式为环间隔基 - 羧酸。BM 17.0744是一种结构上与噻唑烷二酮无关的化合物，在多种II型糖尿病动物模型中已证明其具有降血糖和抗高胰岛素血症的效力。该抗糖尿病作用与疾病的遗传背景、性别和动物种类无关。在ob/ob小鼠单次和第四次口服0.3、1和3mg/kg/d后，24小时血糖曲线呈剂量和时间依赖性改善。在db/db小鼠第五次口服3、10、30和100mg/kg/d后，发现血糖过高呈剂量依赖性降低（分别为10%、15%、28%和66%）。在黄色KK小鼠第五次口服0.3、1、3和10mg/kg/d后，高胰岛素血症呈剂量依赖性降低，分别降低1%、24%、34%和66%。在以10mg/kg/d BM 17.0744预处理14天的肥胖fa/fa大鼠的正常血糖 - 高胰岛素钳夹研究中，总体葡萄糖代谢主要更高。糖尿病和胰岛素抵抗动物的数据表明胰岛素作用得到改善，体外胰岛素效应增强也支持这一点。在糖尿病和代谢健康的动物中没有低血糖风险的证据。代谢健康大鼠血清中的甘油三酯（TG）和胆固醇降低，db/db小鼠的血脂也降低，这表明这种作用与糖尿病状态的改善无关。BM 17.0744在糖尿病和健康动物中的降脂作用显示了其另一特性。由于其抗糖尿病和降脂效力，该物质在治疗代谢综合征方面具有重大意义。大鼠体内脂质的减少与肝脏中肉碱乙酰转移酶活性的剂量依赖性增加至约100倍（12.5mg/kg/d）相关。这与小型啮齿动物的肝肿大一起可能表明过氧化物酶体增殖，这是一种被认为具有物种特异性的现象。对于包括贝特类药物在内的其他类化合物，其与人类的相关性已有充分记录。在大鼠中口服BM 17.0744 4周后，未观察到噻唑烷二酮类胰岛素增敏剂的特定副作用，如体重和心脏重量增加。总体而言，在所有测试物种中，BM 17.0744在药理剂量范围内耐受性良好。
