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

具有抗肥胖作用的无机含锌药物的开发

基本信息

批准号：
20590551
负责人：
YASUI Hiroyuki
金额：
$ 3.08万
依托单位：
Kyoto Pharmaceutical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2008
资助国家：
日本
起止时间：
2008 至 2010
项目状态：
已结题

项目摘要

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.

基于配体和配合物的合成、物理化学性质的评价、体外试验如抑制新鲜分离的大鼠脂肪细胞的游离脂肪酸、增强3 T3-L1培养的脂肪细胞中的脂联素分泌、抑制大鼠小肠的α-葡萄糖苷酶和猪胰的脂肪酶、使用2型糖尿病模型KKAy小鼠的体内动物实验。从这些研究中，发现其配体衍生自天然化合物的锌-硫杂卓酮络合物通过口服施用比通常表现出更强的降血糖作用。然后，通过测定放射性标记的锌示踪剂（^ Zn）来检查该络合物的药代动力学（PK）分析和器官分布<65>，以评价靶器官，并且另外研究了减肥作用。锌硫卓酮复合物分布于肝脏和肌肉，促进葡萄糖代谢的改善;然而，这种复合物不分布于脂肪组织，没有表现出任何作用。这一性质没有导致减肥作用，但有副作用的甘油三酯血症，这可能是由于不充分的转移和积累的甘油三酯产生的肝脏脂肪组织。在今后的研究中，我们需要在PK-药效学分析的基础上，设计和开发具有肝脏、肌肉和脂肪组织分布和作用特性的锌配合物。