Development of CoMFA models of affinity and selectivity to angiotensin II type-1 and type-2 receptors

The renin-angiotensin system (RAS) is of major importance in cardiovascular and renal regulation and has been an attractive target in drug discovery for a long time. The main receptors involved in the RAS are the Angiotensin type-1 (AT1) and type-2 (AT2) receptors, which are both activated by the endogenous octapeptide angiotensin II (AngII). This study describes the development of 3D-QSAR models for AT1 and AT2 receptor affinity and AT1/AT2 receptor selectivity using CoMFA. A data set of 244 compounds, based on the triazolinone and quinazolinone structural classes was compiled from the literature. Before CoMFA could be performed, an alignment rule for the two structural classes was defined using the pharmacophore-searching program DISCOtech. Models were validated using a test set obtained by dividing the data set into a training set and test set using hierarchical clustering, based on the CoMFA fields, AT1-, AT2-receptor affinities, and AT1/AT2 selectivity values. Predictive models with good statistics could be developed both for AT1 and AT2 receptor affinity as well as selectivity towards these receptors.