1-[[4-(AMINOALKOXY)PHENYL]SULFONYL]INDOLIZINES - A NOVEL CLASS OF CALCIUM-ENTRY BLOCKERS - RELATIONSHIPS BETWEEN CHEMICAL-STRUCTURE, STEREOELECTRONIC PROPERTIES AND ANTICALCIC ACTIVITY

The solid-state structures of a series of 1-[[4-(aminoalkoxy)phenyl]su lfonyl]indolizines have been determined by X-ray analysis. These molec ules are known to be representative of a novel class of calcium entry blockers characterized by a new binding site associated with the L-typ e calcium channel. Previous 2-dimensional structure-activity relations hip studies have shown that 1-sulfonylindolizines substituted in the 2 position by an isopropyl group and possessing an aralkylamine substru cture were among the most potent calcium antagonists. A comparative st udy of the 3-dimensional X-ray structures and the electronic propertie s computed at the ab initio HF level of five 1-sulfonyl, 2-alkyl and 2 -phenylindolizine calcium antagonists presenting different types of am ine substructures indicates important similarities within the series. This has led us to propose the first pharmacophoric elements for this kind of compound.