Novel N- and 4-substituted 1,4-dihydropyridines with a C2-symmetric molecular scaffold have been profiled as highly active modulators of the transmembrane efflux pump P-glycoprotein (P-gp, ABCB1) in an exclusively P-gp overexpressing cell line model. Structure–activity relationships have been discussed for varied substituents of both the N- and the 4-residue. The influence of potential hydrogen bond acceptor functions has been characterized in relation to the number and position of the substituents. Cellular toxicity has been closely considered and the P-gp substrate properties are suggested as the limiting molecular properties of known P-gp modulators. The non-toxicity and non-substrate properties of our novel inhibitors qualify this novel compound class as a prospective tool to effectively combat the efflux pump-mediated cellular resistance of anticancer drug substrates, as could be demonstrated in the first in vitro studies.
