A quantitative structure-activity relationship study on a novel class of calcium-entry blockers: 1-[{4-(aminoalkoxy)phenyl}sulphony1]indolizines

A quantitative structure-activity relationship (QSAR) study has been made on two different series of 1-[{4-(aminoalkoxy)phenyl}sulphonyl]indolizines acting as calcium entry blockers, using some physicochemical and structural parameters. Two different assays were reported for both the series: (IC50)A, referring to the molar concentration of the compound required to reduce [H-3] nitrendipine binding by 50%, and (IC50)(B), referring to that required to block Ca2+ induced concentration of K+ depolarised rat aorta by 50%. For series 1, where the 2-position substituents of indolizine ring were varied along with the aminoalkoxy moieties of the phenyl ring, the QSAR analysis shows that the 2-position substituents can equally affect both the activities through their hydrophobic and electronic properties and the aminoalkoxy moiety through some steric effects. For series 2, where the indolizine ring has been replaced by varying heterocyclic rings, along with the changes in aminoalkoxy moiety of the phenyl ring, the QSAR exhibits that these different heterocyclic rings affect both the activities through some steric roles, altering the conformations of the receptors from system A to system B. Among the different heterocyclic rings, the N-substituted indole ring is shown to be more conducive to both the activities than any other ring. However, a 5-membered ring is indicated to be less effective than a 9- or 10-membered ring for activity B. Additionally, the amino moieties having phenyl ring with methoxy groups at 3,4,and 5-positions are shown to favour both A and B activities. (C) 2003 Editions scientifiques et medicales Elsevier SAS. All rights reserved.