Potent HIV Protease Inhibitors Containing a Novel (Hydroxyethyl)amide Isostere

A series of HIV protease inhibitors containing a novel (hydroxyethyl)amidosuccinoyl core has been synthesized. These peptidomimetic structures inhibit viral protease activity at low nanomolar concentrations (IC50 < 10 nM for HIV-1 protease). The inhibition constant (K i) for inhibitor 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 concentrations (EC50) = 3.7−35 nM. This series of inhibitors was found to exhibit poor bioavailability (