A NOVEL CLASS OF CALCIUM-ENTRY BLOCKERS - THE 1-[[4-(AMINOALKOXY)PHENYL]SULFONYL]INDOLIZINES

The synthesis and initial biological evaluation of a series of 1-sulfo nylindolizines is described. These compounds have been shown to be rep resentatives of a novel class of potent, slow-channel calcium antagoni sts. All compounds were found to be at least as active as the referenc e calcium antagonists verapamil and cis-(+)-diltiazem. Structure-activ ity relationship studies have shown that all compounds possessing an a ralkyl group in the amine moiety and an isopropyl or cyclopropyl group at the 2 position of the indolizine are among the most potent calcium antagonists known outside the 1,4-dihydropyridine series. The IC50 va lues for the inhibition of [H-3]nitrendipine binding vary between 0.19 and 4.5 nM whereas the IC50 value for nifedipine is 2.5 nM. One of th e compounds in this group (9ab) has now been selected for clinical dev elopment.