Studies on orally active antidiabetic vanadium complexes with low toxicity and long-term action

我们研究了低毒长效口服抗糖尿病钒酰配合物的开发，以了解配合物-活性关系的结构。研究分以下几个步骤进行。(1)不同配位模式钒基配合物的制备及结构分析。(2)利用大鼠脂肪细胞体外评价该复合物对游离脂肪酸的抑制作用；(3)体内评价该复合物对链脲佐菌素（STZ）诱导的胰岛素依赖型糖尿病（IDDM）大鼠或非胰岛素依赖型糖尿病（NIDDM）小鼠通过ip注射或口服给药的可能性。从2年的实验结果来看，我们发现vo （v_2o_2）配位的vanadyl-picolinate配合物口服具有良好的血糖调节作用。然后，我们扩大了我们的工作，以寻找更好的配合物，并发现了低毒性和长期作用的钒-6-甲基-吡啶甲酸盐配合物。并从钒的器官分布和药代动力学方面分析了配合物的作用机理。有趣的是，当通过ip注射或口服给药时，发现该复合物对NIDDM小鼠有效。另一方面，钒对stz诱导的糖尿病的发展有有效的保护作用。在此基础上，发现钒化合物对实验动物IDDM和NIDDM均有治疗作用，并对IDDM的发生有保护作用。

We studied on development of orally active antidiabetic vanadyl complexes with low toxicity and long-term action to know the structure of the complex-activity relationship. Research was performed in the following steps. (1) Preparation of vanadyl complexes with different coordination modes and analysis of the structure. (2) In vitro evaluation of the complex using rat adipocytes in terms of suppression of free fatty acids and (3) in vivo evaluation of the possible complex, which was given to streptozotocin (STZ)-induced insulin-dependent diabetes mellitus (IDDM) rats or none-insulin-dependent diabetes mellitus (NIDDM) mice by ip injection or oral administration.From the results for 2 years, we found that a vanadyl-picolinate complex with vo (v_2o_2) coordination mode has a good blood glucose normalizing effect on oral administration. Then we extended our work to find better complexes and found vanadyl-6-methyl-picolinate complex with low toxicity and long-term action when administered orally. The action mechanism of the complex was also analyzed in terms of vanadium organ distribution and pharmacokinetics. Interestingly, the complex was found to be effective on NIDDM mice when given by ip injection or oral administration. On the other hand, vanadium was found to be effective on the protection of development of STZ-induced diabetes. On the basis of the results, vanadium compounds were found to be effective to treat both IDDM and NIDDM in experimental animals as well as to protect the development of IDDM.