2‘,6‘-Dimethylphenoxyacetyl:  A New Achiral High Affinity P<INF>3</INF>-P<INF>2</INF> Ligand for Peptidomimetic-Based HIV Protease Inhibitors

Starting from palinavir (<BO>1</BO>), our lead HIV protease inhibitor, we have discovered a new series of truncated analogues in which the P<INF>3</INF>-P<INF>2</INF> quinaldic-valine portion of <BO>1</BO> was replaced by 2‘,6‘-dimethylphenoxyacetyl. With EC<INF>50</INF>'s in the 1−2 nM range, some of these compounds are among the most potent inhibitors of HIV replication in vitro, reported to date. One of the most promising members in this series (compound <BO>27</BO>, BILA 2185 BS) exhibited a favorable overall pharmacokinetic profile, with 61% apparent oral bioavailability in rat. X-ray crystal structures and molecular modeling were used to rationalize the high potency resulting from incorporation of this structurally simple, achiral ligand into the P<INF>3</INF>-P<INF>2</INF> position of hydroxyethylamine-based HIV protease inhibitors.