Design of copper-based anti-inflammatory drugs.

It has been shown that the inflammation associated with rheumatoid arthritis can be reduced using copper complexes. In order to improve the bioavailability of copper and hence efficacy of these complexes we have synthesized three different series of ligands, each having different characteristics. Thermodynamic results for copper(II) complexes for these polyamino, diaminodiamido and triaminodiamido ligands are presented. The polyamino ligands form the most stable complexes in vivo but tissue distribution studies in mice show that [Cu(3,6,9,12-tetraazatetradecanedioate)] is excreted rapidly, unchanged in the urine. The diamino ligand complexes are much less stable than their polyamino analogues and animal studies using [Cu(N,N'-bis[2-(dimethylamino)ethyl]-ethanediamide)H2] indicate that the complex dissociates in vivo and is excreted slowly via the liver. The triaminodiamido copper(II) complexes are approximately 2 log units more stable than their diamino analogues. Computer simulation calculations indicate that these complexes are also likely to dissociate in plasma. Measured partition coefficients, however, suggest the possibility of dermal absorption.