QSAR study of substituted 2-pyridinyl guanidines as selective urokinase-type plasminogen activator (uPA) inhibitors.

A quantitative structure-activity relationship analysis was conducted on two different series of pyridinylguanidines acting as inhibitors of urokinase-type plasminogen activator using QuaSAR descriptors of molecular modeling software MOE. Multiple linear regression analysis following a stepwise scheme was employed to generate QSARs that relate molecular descriptors to uPA inhibitory activity data of the title compounds. Among the several QSARs generated by MLR analysis, the best models were selected on the basis of their statistical significance and predictive potential. The interpretation of the selected QSAR models suggest that uPA inhibitory activity of compounds in series 1 is influenced by their molecular shape, molecular flexibility and halogen atoms in the molecule whereas the uPA inhibitory potency of compounds in series 2 is dependent on molecular lipophilicity, number of double bonds and spatial orientation of bulky substituents in the molecule.