Regression analyses using the Free-Wilson technique were applied to the anti-inflam-matory effect and the acute toxicity of 57 1, 3, 5-trisubstituted 2, 4, 6-trioxoperhydropyrimidine derivatives. Models for the orientation of substituents on the "receptor site" are presented. A significant correlation was obtained by assuming that one of the N-substituents with a high hydrophobicity always locates at a particular binding site. Further analysis of the contributions of substituents at the 5-position using the free energy related hydrophobic parameter, π revealed that acute toxicity increases with an increase in the hydrophobicity of the 5-substituents. 1-Cyclohexyl-5-butyl or -allyl derivatives seemed to be the most suitable anti-inflammatory agents in terms of their high activity and low toxicity.
