2 ',6 '-dimethylphenoxyacetyl: A new achiral high affinity P-3-P-2 ligand for peptidomimetic-based HIV protease inhibitors

Starting from palinavir (1), our lead HIV protease inhibitor, we have disco vered a new series of truncated analogues in which the P-3-P-2 quinaldic-va line portion of 1 was replaced by 2',6'-dimethylphenoxyacetyl. With EC50's in the 1-2 nM range, some of these compounds are among the most potent inhi bitors of HIV replication in vitro, reported to date. One of the most promi sing members in this series (compound 27, BILA 2185 BS) exhibited a favorab le overall pharmacokinetic profile, with 61% apparent oral bioavailability in rat. X-ray crystal structures and molecular modeling were used to ration alize the high potency resulting from incorporation of this structurally si mple, achiral ligand into the P-3-P-2 position of hydroxyethylamine-based H IV protease inhibitors.