POTENT HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 PROTEASE INHIBITORS THAT UTILIZE NONCODED D-AMINO ACIDS AS P-2 P-3 LIGANDS/

Noncoded D-amino acids have been designed to replace the quinaldic ami de-asparaginyl moiety (P-2/P-3 ligand) found in several potent human i mmunodeficiency virus (HIV) protease inhibitors such as LY289612. The substituted nitrogen, optimally an N-methanesulfonyl moiety, served as a CH2CONH2 (asparagine side chain mimic), while the amino acid side c hain became the backbone and P-3 ligand of these novel inhibitors. Com pounds derived from S-aryl-D-cysteine proved to be patent HIV protease inhibitors which also exhibited potent whole cell antiviral activity. Oxidation of the cysteines to the sulfoxide or sulfone oxidation stat es resulted in significant improvements in potency. For example, the c ompound derived from N-(methylsulfonyl)-2-S-naphthylcysteine sulfone, 17c, was a 3.5 nM inhibitor of HIV protease which inhibited the spread of virus in MT4 cells with an IC50 = 4.3 nM. Compounds 17c,g,i were f ound to be orally bioavailable in a rat model.