Design and discovery of RWJ 22108 - A novel bronchoselective calcium channel blocker

A series of cyclic sulfone dihydropyridines ranging in sulfone ring size from five to nine membered have been evaluated for calcium antagonist activity. Increasing the sulfone ring size from 5 to 8 membered resulted in a two orders of magnitude in vitro potency increase. Aromatic substitution which favored tracheal effects over aortic effects was found to be 2-NO₂ and 2-Cl, 6-F. The ester side chain which was found to maximize in vivo activity was the N-benzyl-N-methyl aminoethyl moiety. Combination of all these structural features resulted in RWJ 22108, a bronchoselective calcium channel blocker which preclinically exhibits an antiasthmatic profile.