QSAR study of substituted 2-pyridinyl guanidines as selective urokinase-type plasminogen activator (uPA) inhibitors

Abstract

A quantitative structure–activity relationship analysis was conducted on two different series of pyridinylguanidines acting as inhibitors of urokinase-type plasminogen activator using QuaSAR descriptors of molecular modeling software MOE. Multiple linear regression analysis following a stepwise scheme was employed to generate QSARs that relate molecular descriptors to uPA inhibitory activity data of the title compounds. Among the several QSARs generated by MLR analysis, the best models were selected on the basis of their statistical significance and predictive potential. The interpretation of the selected QSAR models suggest that uPA inhibitory activity of compounds in series 1 is influenced by their molecular shape, molecular flexibility and halogen atoms in the molecule whereas the uPA inhibitory potency of compounds in series 2 is dependent on molecular lipophilicity, number of double bonds and spatial orientation of bulky substituents in the molecule.

Keywords::

• MOE
• QSAR
• pyridinyl guanidines
• uPA
• inhibitors

Acknowledgements

One of the authors, C. Karthikeyan wishes to thank CSIR, India for providing a senior research fellowship. The authors wish to thank Tata Elxsi for providing MOE software for the study. Grateful acknowledgements to Prof. P. B. Sharma, Vice Chancellor, Rajiv Gandhi Technical University, Bhopal and Director, SGSITS, Indore for the experimental facilities provided. The authors also wish to thank Prof. L.B. Kier and Prof. M. Petitjean for providing reprints of their research works. This research work is funded by grant from All India Council of Technical Education, New Delhi, India.