Development of inorganic zinc-containing medicines with anti-obesity action

在配体和络合物合成、理化性质评价、体外抑制新鲜分离大鼠脂肪细胞游离脂肪酸、促进3T3-L1脂肪细胞分泌脂联素、抑制大鼠小肠α-葡萄糖苷酶和猪胰腺脂肪酶等体外实验的基础上，开发了几种抗糖尿病锌(II)配合物。从这些研究中发现，配体来自天然化合物的锌-硫代托酮络合物，在口服时表现出比通常更强的降血糖作用。然后，通过放射性标记锌示踪剂(65&gt；锌)的测定，对该复合体的药代动力学(PK)分析和器官分布进行检测，以评价其靶器官，并观察其减肥作用。锌-硫代托酮络合物分布于肝脏和肌肉，促进糖代谢的改善，但不分布于脂肪组织，无作用。这一特性并没有导致减肥作用，而是引起了高脂血症的副作用，这可能是由于肝脏中产生的甘油三酯向脂肪组织转移和积累不足所致。在未来的研究中，我们需要在PK-药效学分析的基础上，设计和开发对肝脏、肌肉和脂肪具有分布和作用性质的锌配合物。

Several anti-diabetic zinc(II) complexes have been developed on the basis of synthesis of ligands and complexes, evaluation of physico-chemical properties, in vitro assays such as inhibition of free fatty acid from freshly isolated rat adipocytes, enhancement of adiponectine secretion in 3T3-L1 cultured adipocytes, inhibition of alpha-glucosidase from rat small intestine and lipase from porcine pancreas, in vivo animal experiments using type 2 diabetic model KKAy mice. From these studies, zinc-thiotropone complex of which ligand is derived from natural compounds was found to exhibit more hypoglycemic action than usual by oral administration. Then, pharmacokinetic (PK) analysis and organ distribution of this complex were examined by determination of radio-labeled zinc tracer (^<65>Zn) in order to evaluation the target organs, and in addition anti-obesity action was investigated. Zinc-thiotropone complex was distributed to liver and muscle which enhanced the improvement of glucose metabolism; however, this complex was not distributed to adipose tissues and exhibited no action. This disposition property led no anti-obesity action but side-effect of hyperlipemia, which might be caused by insufficient transfer and accumulation of triglyceride produced in liver to adipose tissues. In the future study, we need to molecular-design and develop zinc complexes with distribution and action properties to liver, muscle and adipose on the basis of PK-pharmacodynamic analysis.