The synthesis and SAR of HIV-1 protease inhibitors contg. novel P2 structural elements are presented. The inhibitors were designed having hydrogen bond accepting P2 substituents to probe potential favorable interactions to Asp-29/Asp-30 of the HIV-1 protease backbone. Several inhibitors were synthesized from an L-Val Me amide P2 motif by appending hydrogen bonding moieties from either the iso-Pr side-chain or from the Me amide portion. The most promising inhibitors I and II displayed Ki values of 1.0 nM and 0.7 nM resp. and EC50 values in the MT4 cell-based assay of 0.17 micro M and 0.33 micro M resp., a slight loss in potency compared to the lead inhibitor. These inhibitors were also tested against an HIV protease inhibitor resistant strain carrying the M46I, V82F, and I84V mutations. Inhibitors I and II displayed a 3 and 4 fold change resp. compared with HIV wild type, whereas the lead inhibitor showed a higher 9 fold change. This study further demonstrate the chem. tractability of the approach where various P2 substituents can be introduced in just one chem. step from lactone 21 enabling facile modifications of the overall properties in this inhibitor class. [on SciFinder (R)]The synthesis and SAR of HIV-1 protease inhibitors contg. novel P2 structural elements are presented. The inhibitors were designed having hydrogen bond accepting P2 substituents to probe potential favorable interactions to Asp-29/Asp-30 of the HIV-1 protease backbone. Several inhibitors were synthesized from an L-Val Me amide P2 motif by appending hydrogen bonding moieties from either the iso-Pr side-chain or from the Me amide portion. The most promising inhibitors I and II displayed Ki values of 1.0 nM and 0.7 nM resp. and EC50 values in the MT4 cell-based assay of 0.17 micro M and 0.33 micro M resp., a slight loss in potency compared to the lead inhibitor. These inhibitors were also tested against an HIV protease inhibitor resistant strain carrying the M46I, V82F, and I84V mutations. Inhibitors I and II displayed a 3 and 4 fold change resp. compared with HIV wild type, whereas the lead inhibitor showed a higher 9 fold change. This study further demonstrate the chem. tractability of the approach where various P2 substituents can be introduced in just one chem. step from lactone 21 enabling facile modifications of the overall properties in this inhibitor class. [on SciFinder (R)]