Application of molecular connectivity and electro-topological indices in quantitative structure-activity analysis of...

Factor Xa and thrombin, two critical pro-coagulant enzymes of the clotting cascade, are the primary target of current anticoagulation research that aims to develop potent, orally bioavailable, synthetic small-molecule inhibitors. To determine structural features that might play important roles in factor Xa and thrombin recognition and oral bioavailability, quantitative structure-activity and structure-property analyses were performed on the factor Xa and thrombin inhibition data and Caco-2 cell-permeability data of 3-substituted pyrazole-5-carboxamides reported by Pinto et al. (J. Med. Chem. 2001, 44, 566). The factor Xa and thrombin inhibition potencies, and Caco-2 cell permeability of the 3-substituted pyrazole-5-carboxamides could be quantitatively described through molecular connectivity and atom level E-state indices. Different quantitative structure-activity and structure-property models were derived for each of the three biological properties. The models are statistically relevant with correlation coefficients of at least 0.9, and contain only two or three molecular descriptor variables. The study demonstrates the use of molecular connectivity and E-state indices in understanding factor Xa and thrombin inhibition. In addition, the models may be useful for predictive purposes in generating molecules with better potency, specificity, and oral bioavailability.