Application of Theoretical Drug Design Methodology to a Series of Diuretics

Abstract

Linear free energy methodology and molecular modelling were used to aid the optimization of the structure of a set of (aminomethylaryloxy) acetic acid esters. Series design strategy based on linear free energy relationships allowed the optimization within a small set of analogues of the substituent on the amino group and that on the ester. The amino group tolerates only small substituents, whereas all esters are biologically equivalent. Molecular modelling revealed that the oxyacetate side chain and the atom that bridges the two aromatic rings are in regions in space that forbid large substituents.