QSAR modelling of pancreatic β-cell KATP channel openers R/S-3,4-dihydro-2,2-dimethyl-6-halo-4-(substituted phenylaminocarbonylamino)-2H-1-benzopyrans using MLR–FA techniques

Potassium (K+) channel openers are a diverse group of compounds which are used for the treatment of diseases like angina pectoris, hypertension, congestive heart failure, anti-hypoglycemic (insulinoma), bronchial asthma, etc. R/S-3,4-dihydro-2,2-dimethyl-6-halo-4-(substituted phenylaminocarbonylamino)-2H-1-benzopyrans are a new series of ATP-sensitive potassium (KATP-pβ) channel openers selective towards pancreatic β-cells. QSAR modelling was done on these series of compounds to find a more active and selective KATP-pβ channel opener selective towards β-cells of pancreatic tissues. Wang–Ford charges, partition coefficient, molar refractivity, principle moment of inertia at X, Y and Z axes are used as predictor variables and logarithm of percentage of residual insulin secretion is treated as response variable for the modelling. Multiple linear regressions with factor analysis were performed to develop QSAR models. Four equations were obtained using different combinations of the predictor variables based on factor loadings. Regression coefficients of all descriptors used are significant at more than 95% level. Results showed that Wang–Ford charges on atom numbers 11, 17, 18, 19 and 21 are important for the inhibition of residual insulin secretion. The presence of electron withdrawing group at m- and p-position of phenyl ring B is required for the inhibition. The energy minimized geometry of the most active compound supported our modelling.

Graphical abstractTo search for more active and selective potassium (KATP-pβ) channel opener for the pancreatic tissues, QSAR modelling was performed on R/S-3,4-dihydro-2,2-dimethyl-6-halo-4-(substituted phenylaminocarbonylamino)-2H-1-benzopyrans using MLR–FA techniques.Figure optionsDownload full-size imageDownload as PowerPoint slide