POTENT HIV PROTEASE INHIBITORS - THE DEVELOPMENT OF TETRAHYDROFURANYLGLYCINES AS NOVEL P(2)-LIGANDS AND PYRAZINE AMIDES AS P(3)-LIGANDS

A series of protease inhibitors bearing constrained unnatural amino ac ids at the P2-position and novel heterocycles at the P3-position of co mpound 1 (Ro 31-8959) were synthesized, and their in vitro enzyme inhi bitory and antiviral activities were evaluated. Replacement of P2-aspa ragine of compound 1 with (2S,3'R)-tetrahydrofuranylglycine resulted i n improvement in enzyme inhibitory as well as antiviral potencies (com pound 23). Interestingly, incorporation of (2S,3'S)-tetrahydrofuranylg lycine at the P2-position proved to be less effective. The resulting c ompound 24 was 100-fold less potent than the 2S,3R-isomer (compound 23 ). This stereochemical preference indicated a hydrogen-bonding interac tion between the tetrahydrofuranyl oxygen and the residues of the S2-r egion of the enzyme active site. Furthermore, replacement of P3-quinol inoyl ligand of 1 with various novel heterocycles resulted in potent i nhibitors of HIV proteases. Of particular interest, compound 2 with (2 S,3'R)-tetrahydrofuranylglycine at P2 and pyrazine derivative at P3 is one of the most potent inhibitors of HIV-1 (IC50 value 0.07 nM) and H IV-2 (IC50 value 0.18 nM) proteases. Another important result in this series is the identification of compound 27 in which the P2-P3-amide c arbonyl has been removed. The resulting compound 27 has exhibited impr ovement in antiviral potency while retaining the enzyme inhibitory pot ency similar to compound 1.