Quantitative structure activity relationship studies of diarylimidazoles as selective COX-2 inhibitors

Abstract

Quantitative structure activity relationship approach using stepwise regression analysis has been applied to a series of 63 diarylimidazole derivatives as selective COX-2 inhibitors. For this purpose 49 compounds have been taken as training set and the rest as test set. These studies have produced good predictive models with high regression constant (r = 0.927), low standard deviation (0.279) and standard error of regression (0.30). A good correlation of various parameters like hydrophobicity (<img src='/image/spc_char/pi.gif'>), electrophilicity (σ) and van der Waal’s volume of various substituents has been established with COX-2 inhibitory activity. The impact of these structural parameters on the selectivity ratio (log COX-1/COX-2) has also been analyzed. The resulting correlation revealed that substitution at position A₃ with groups having low van der Waal’s volume and high <img src='/image/spc_char/pi.gif'> and σ values and substitution at A₅ and A₄with groups having high <img src='/image/spc_char/pi.gif'> and σ values are significant in increasing COX-2 inhibitory activity. Parameters for COX-2 enzyme selectivity have also been identified and on the basis of obtained correlation certain new compounds have been designed with much higher selectivity as COX-2 enzyme inhibitors in comparison to compounds reported in literature with retention of high inhibitory potency.