Synthesis and evaluation of delta lactams as nonpeptide HIV-protease inhibitors

The cyclization of the linear hydroxyethylene isostere based HIV-PR inhibitors gave the delta lactam XQ921, which was found to have a Ki = 9.4 uM. It is proposed that a major reason for the weaker potency of the lactam XQ921 compared to cyclic urea based inhibitors is the lack of a P1′ substituent that could interact with the S1′ pocket of HIV-PR.