Exploring selectivity requirements for COX-2 versus COX-1 binding of 2-(5-phenyl-pyrazol-1-yl)-5-methanesulfonylpyridines using topological and physico-chemical parameters

Abstract

Considering the current need for development of selective cyclooxygenase-2 (COX-2) inhibitors, an attempt has been made to explore physico-chemical requirements of 2-(5-phenyl-pyrazol-1-yl)-5-methanesulfonylpyridines for binding with COX-1 and COX-2 enzyme subtypes and also to explore the selectivity requirements. In this study, E-states of different common atoms of the molecules (calculated according to Kier & Hall), first order valence connectivity and physico-chemical parameters (hydrophobicity π, Hammett σ and molar refractivity MR of different ring substituents) were used as independent variables along with suitable dummy parameters in the stepwise regression method. The best equation describing COX-1 binding affinity [n = 25, Q² = 0.606, Ra²= 0.702, R² = 0.752, R = 0.867, s = 0.447, F = 15.2 (df 4, 20)] suggests that the COX-1 binding affinity increases in the presence of a halogen substituent at R₁ position and a p-alkoxy or p-methylthio substituent at R₂ position. Furthermore, a difluoromethyl group is preferred over a trifluoromethyl group at R position for the COX-1 binding. The best equation describing COX-2 binding affinity [n = 32, Q² = 0.622, Ra²= 0.692, R² = 0.732, R = 0.856, s = 0.265, F = 18.4 (df 4, 27)] shows that the COX-2 binding affinity increases with the presence of a halogen substituent at R₁ position and increase of size of R₂ substituents. However, it decreases in case of simultaneous presence of 3-chloro and 4-methoxy groups on the phenyl nucleus and in the presence of highly lipophilic R₂ substituents. The best selectivity relation [n = 25, Q² = 0.455, Ra²= 0.605, R² = 0.670, R = 0.819, s = 0.423, F = 10.2 (df 4, 20)] suggests that the COX-2 selectivity decreases in the presence of p-alkoxy group and electron-withdrawing para substituents at R₂ position. Again, a trifluoro group is conducive for the selectivity instead of a difluoromethyl group at R position. Furthermore, branching may also play significant role in determining the selectivity as evidenced from the connectivity parameter.