Dimeric 4-Aryl-1,4-dihydropyridines: development of a third class of nonpeptidic HIV-1 protease inhibitors

Cross-resistance development against most peptidic HIV-1 protease inhibitors (PI) forces the development of nonpeptidic alternatives. The classes of nonpeptidic protease inhibitors was limited so far to cyclic ureas and 4-hydroxy-2-pyrones with problems of limited bioavailability by extensive metabolism and protein binding. Cage dimeric 4-aryl-1,4-dihydropyridines have been developed as third class of nonpeptidic PIs. In the following synthesis, molecular modeling and biological activities of a first series of the novel PIs are reviewed. Bioavailability of the dimers will not be limited by protein binding and metabolism as far as evaluated.