Investigation of the lipophilic behaviour of some thiazolidinediones: Relationships with PPAR-γ activity

Various lipophilicity aspects of five well-known PPAR-γ ligands, belonging to the thiazolidinedione (TZD) class, ciglitazone (CSZ), troglitazone (TGZ), netoglitazone (NGZ) and the ampholytic pioglitazone (PGZ) and rosiglitazone (RGZ), have been explored. The compounds were found to be highly lipophilic as assessed by direct octanol–water partitioning experiments and further confirmed by reversed phase HPLC measurements under different conditions. Immobilised artificial membrane (IAM) chromatographic indices were also determined as an alternative expression of lipophilicity. They were found to show less diversity forming two clusters. Experimental log D/log P values were compared to those predicted by three widely used calculation systems. For the two ampholytic TZDs, the lipophilicity and retention/pH profiles were established over a broad pH range and compared to the corresponding calculated profiles. Lipophilicity indices derived under the different conditions were further compared to biological activity, concerning in vitro transactivation (pEC50) and binding affinity (pKi) data, taken from literature. The most active TZD (RGZ) in both transactivation and binding assay proved to be the less lipophilic analogue. An equation relating pEC50 data to experimental log D7.4 or reversed-phase log kw values could be established, while pKi data did not lead to satisfactory correlation.