QSAR study of some cyclobutenediones as CCR1 antagonists by artificial neural networks based on principal component analysis

A quantitative structure activity relationship [QSAR] model based on artificial neural networks [ANN] was developed to study the activities of 29 derivatives of 3-amino-4-[2-[2-[4-benzylpiperazin-1-yl]-2-oxoethoxy] phenylamino] cyclobutenedione as C-C chemokine receptor type 1[CCR1] inhibitors. A feed-forward ANN with error back-propagation learning algorithm was used for model building which was achieved by optimizing initial learning rate, learning momentum, epoch and the number of hidden neurons. Good results were obtained with a Root Mean Square Error [RMSE] and correlation coefficients [R[2]] of 0.189 and 0.906 for the training and 0.103 and 0.932 prediction sets, respectively. The results reflect a nonlinear relationship between the Principal components obtained from calculated molecular descriptors and the inhibitory activities of the investigated molecules

Synthesis and evaluation of calcium channel antagonist activity of new 1, 4- dihydropyridines containing phenylamineimidazolyl substitute in guinea-pig ileal smooth muscle

Background: 1,4-dihydropyridines are a class of drugs which are used in the treatment of some cardiovascular disorders. The prototype, Nifedipine, does not have optimal pharmacokinetic and pharmacodynamic properties. Several new derivatives of 1, 4-dihydropyridine have been produced and pharmacologically evaluated in order to find drugs with better pharmacological properties. Among them, those with a substituted heteroaromatic ring in the C4 position of the 1, 4-dihydropyridine ring, instead of the phenyl ring in Nifedipine, are most considered. In this study, eight novel derivatives of this class with "2-methylthio-1-[phenylamino]imidazole-5-yl" in the C4, C3 and C5 positions were prepared and evaluated as calcium channel antagonist agents

Methods: to prepare these compounds, Hantzsch method for the synthesis of 1, 4-dihydropyridine derivatives was deployed. An aldehyde was reacted with appropriate acetoacetate ester and ammonium acetate. This aldehyde was prepared in three steps. Cumulative doses were applied to determine the relaxing effect of the compounds on the longitudinal smooth muscle of male albino guinea pigs

Results: chemical structures of the compounds were characterized by 1H nuclear magnetic resonance, infrared and mass spectroscopy. The IC50 of each compound was graphically determined from the concentration-response curves

Conclusions: two compounds were more active than Nifedipine. Both had lipophilic ester groups with low steric hindrance that met the merits of a better receptor binding of 1, 4-dihydropyridines. These derivatives have high potential for further study