SC-57666

Quantitative structure activity relationship (QSAR) studies of selective COX-2 inhibitors of commercial interest (drugs in market and on clinical trials) were performed. The COX-2 inhibitory activity (pIC(50)=-logIC(50)) of these twelve compounds was correlated with nineteen descriptors including steric, electronic and constitutional parameters. pIC(50) activity showed high positive correlation with both volume and HOMO (Highest occupied molecular orbital). A Biparametric model was developed that included both these descriptors. The predictive capability (q(2)= 0.66) of this equation was satisfactory. So it can be used to design newer templates or modify existing templates. Volume is an important parameter for the selective COX-2 inhibitory activity, because the secondary pocket in the active site of this enzyme is bigger than the active site of COX-1 enzyme (by 17%). HOMO is a measure of the nucleophilicity of the molecule and a molecule with high HOMO energy is ready to donate its electrons and thus is more reactive than molecule with low values. Binding studies were performed between the COX-2 enzyme and these molecules. The inhibitory activity increased with decrease in binding energy (or interaction energy) between the compounds with the COX-2 enzyme (with a correlation coefficient = -0.65). Calculated Log BBB (Blood Brain barrier), Log P (octonol water partition) and HBD (hydrogen bond donor) values were in the acceptable range (i.e., BBB = -1 to 0.3; LogP= 0 to 5; HBD < 5).

Since the discovery that the anti-inflammatory effects of cyclooxygenase (prostaglandin endoperoxide H(2) synthetase; COX) inhibitors were dependent on their selectivity for the inducible COX-2 isoform over the constitutive COX-1, many efforts have been devoted towards the design of compounds displaying improved COX-2 selectivity. Classical bioisosteres such as CH-CF and CH(2)-S/O substitutions have been extensively used in the design of the classical COX-2 inhibitors, although silicon isosteres have been so far overlooked. The replacement of a carbon by a silicon atom can have beneficial effects in this particular family of compounds, because the increased bond lengths and altered bond angles brought by the sila-substitution might modify their binding mode to the COX enzymes. In order to evaluate such possible benefits, several well-characterized model inhibitors were selected and docked in the murine COX-2 and COX-1 binding sites. The binding energies for the interaction of each model compound with the respective isoenzymes were derived from the docking data. As in previous publications, these were found to correlate closely (r(2) = 0.66 and 0.75 for COX-2 and COX-1, respectively) with experimental inhibitory activities towards the recombinant enzymes gathered from the literature. These relationships allowed the prediction of the inhibitors activity towards both enzyme isoforms, which further permitted the prediction of their selectivity for COX-2 with an acceptable accuracy (cross-validated squared correlation coefficient q(2) = 0.64). These model compounds were theoretically modified by substituting selected carbon atoms by an sp(3) silicon, and further docked in both COX-2 and COX-1 binding sites in order to derive their predicted inhibitory activity for both isoforms. Except in a few cases, the sila-substitution did not significantly increase the inhibitory activity towards COX-2. In most cases however, it produced a significant decrease in the inhibitory activity towards COX-1. These results indicate that isosteric sila-substitutions could be of value in the design of COX inhibitors with improved selectivity for COX-2.