A novel, picomolar inhibitor of human immunodeficiency virus type 1 proteases

The design, synthesis, and molecular modeling studies of a novel series of azacyclic ureas, which are inhibitors of human immunodeficiency virus type 1 (HIV-1) protease that incorporate different ligands for the S-1', S-2, and S-2' substrate-binding sites of HIV-1 protease are described. The synthesis of this series is highly flexible in the sense that the P-1', P-2, and P-2' residues of the inhibitors can be changed independently. Molecular modeling studies on the phenyl ring of the P-2 and P-2' ligand suggested incorporation of hydrogen-bonding donor/acceptor groups at the 3- and 4-positions of the phenyl ring should increase binding potency. This led to the discovery of compound 7f (A-98881), which possesses high potency in the HIV-1 protease inhibition assay and the in vitro MT-4 cell culture assay (K-i = similar to 5 pM and EC(50) = 0.002 mu M). This compares well with the symmetrical cyclic urea 1 pioneered at DuPont Merck.