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]sulfonyl]indolizines have been determined by X-ray analysis. These molecules are known to be representative of a novel class of calcium entry blockers characterized by a new binding site associated with the L-type calcium channel. Previous 2-dimensional structure-activity relationship studies have shown that 1-sulfonylindolizines substituted in the 2 position by an isopropyl group and possessing an aralkylamine substructure were among the most potent calcium antagonists. A comparative study of the 3-dimensional X-ray structures and the electronic properties computed at the ab initio HF level of five 1-sulfonyl, 2-alkyl and 2-phenylindolizine calcium antagonists presenting different types of amine substructures indicates important similarities within the series. This has led us to propose the first pharmacophoric elements for this kind of compound.