Identifying the Structural Features of Pyrazolo[4,3-c]Quinoline-3-ones as Inhibitors of Phosphodiesterase 4: An Exploratory CoMFA and CoMSIA Study

Anand      Gaurav; Vertika      Gautam

doi:10.2174/1573408011309020004

Abstract

Phosphodiesterases (PDEs) are responsible for the hydrolysis of cyclic nucleotides (cAMP and c-GMP). Cyclic nucleotides are important intracellular secondary messengers in cell function, relaying the signals from hormones at specific cell-surface receptors. An increase of cAMP due to the stimulation of adenylyl cyclase or the inhibition of PDEs affects the activity of immune system and inflammatory cells. Thus, PDE4, a cAMP specific PDE, received much attention as a target for the treatment of the diseases like asthma and Chronic Obstructive Pulmonary Disease (COPD). Pyrazolo[4,3-c]quinoline-3-one nucleus has attracted considerable attention recently as PDE4 receptor antagonists which have shown remarkable therapeutic potential in the treatment of asthma and Chronic Obstructive Pulmonary Disease (COPD). In the present study, three dimensional quantitative structure activity relationship (3D QSAR) approach using CoMFA and CoMSIA was applied to a series of 2, 5-dihydropyrazolo [4, 3-c] quinoline-3-ones as PDE4 receptor antagonists. For the purpose, 22 compounds from the series were used to develop and validate models. The robustness of the model was confirmed with the help of leave one out cross-validation method, while the predictive ability of models was tested using a test set containing three molecules. Novel compounds were designed on the basis of results of CoMFA and CoMSIA studies. Designed compounds were evaluated by Docking and Lipinski filters. 3D-QSAR models with high squared correlation coefficient of up to 0.9590 for CoMFA and 0.9740 for CoMSIA were established. Robustness of the models is demonstrated by R2 cv values of up to 0.8600 and 0.8230 for CoMFA and CoMSIA, respectively. Predictive ability of the models is reflected by R2 pred values of 0.865 and 0.926 for CoMFA and CoMSIA respectively. Predicted activity of the designed molecules correlated well with the docking scores and the molecules also passed the Lipinski filters. Developed models highlighted the importance of steric, electrostatic and hydrophobic properties of the molecules for PDE 4 receptor affinity. The designed compounds may serve as lead for the development of newer PDE4 inhibitors based on the 2, 5-dihydropyrazolo [4, 3-c] quinoline-3-one scaffold.

Keywords: Phosphodiesterase, CoMFA, CoMSIA, k-means clustering, enhanced replacement method, replacement method, cAMP. cGMP.