THE DEVELOPMENT OF CYCLIC SULFOLANES AS NOVEL AND HIGH-AFFINITY P(2) LIGANDS FOR HIV-1 PROTEASE INHIBITORS

Design and synthesis of a novel series of protease inhibitors incorporating conformationally constrained cyclic ligands for the S-2-substrate binding site of HIV-1 protease is described. We recently reported urethanes of 3-tetrahydrofuranyl as P-2 ligands for HIV-1 protease inhibitors. Subsequently, we have found that the urethane of 3(S)-hydroxysulfolane further increased the in vitro potency of these inhibitors. Furthermore, introduction of a small 2-alkyl group cis to the 3-hydroxyl group of either heterocyclic system further enhanced enzyme affinity. The cis-2-isopropyl group thus far offered optimum enhancement of the inhibitory properties. This led to the discovery of inhibitor 43 (IC50 3.5 nM, CIC95 50+/-14 nM) of comparable in vitro antiviral potency to the current clinical candidate 1 (Ro 31-8959) but of reduced molecular weight due to the exclusion of the P-3 quinoline ligand. Also, it has been demonstrated that the octahydropyrindene derivative 34 is an effective replacement of the P-1' decahydroisoquinoline derivative.