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

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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.