POTENT HIV PROTEASE INHIBITORS CONTAINING A NOVEL (HYDROXYETHYL)AMIDEISOSTERE

A series of HIV protease inhibitors containing a novel (hydroxyethyl)a midosuccinoyl core has been synthesized. These peptidomimetic structur es inhibit viral protease activity at low nanomolar concentrations (IC 50 < 10 nM for HIV-1 protease). The inhibition constant (K-i) for inhi bitor 19 was determined to be 7.5 pM against HIV-1 and 1.2 nM against HIV-2 proteases, respectively. Several compounds (19-24) inhibited HIV -1 replication in cell culture assays with 50% effective concentration s (Ec(50)) = 3.7-35 nM. This series of inhibitors was found to exhibit poor bioavailability (< 10%) in the rat, following oral administratio n. The synthesis and biological properties of these compounds are disc ussed. In addition, an X-ray structure of one of these inhibitors (23) in complex with HIV-2 protease provides insight into the binding mode of this novel class of HN protease inhibitors.