Studies of Human Immunodeficiency Virus Type 1 (HIV-1) Protease Inhibitors. III. Structure-Activity Relationship of HIV-1 Protease Inhibitors Containing Cyclohexylalanylalanine Hydroxyethylene Dipeptide Isostere

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Systematic replacement of the P₄-P₂ subsites of substrate-based human immunodeficiency virus type 1 protease (HIV-1 PR) inhibitors containing cyclohexylalanylalanine hydroxyethylene dipeptide isostere (Cha-ψ[H.E.]-Ala) at positions corresponding to the scissile sites of substrates was carried out. The structure-activity relationship revealed that compounds with the combination of hydrophilic P₃ and β-branched hydrophobic P₂ amino acids generally showed strong inhibitory activity against HIV-1 PR. In particular, compounds 4 (Boc-Orn-Val-Cha-ψ[H.E.]-Ala-NHBuⁿ; Buⁿ=n-butyl, K_i=11 nM) and 6 (Z-Orn-Val-Cha-ψ[H.E.]-Ala-NHBuⁿ, K_i=8 nM) exhibited good enzyme selectivity, possessing no significant inhibitory activities toward closely related aspartic proteases, pepsin, cathepsin D, and renin. As a possible model system for evaluating these compounds, anti-retroviral (anti-Mo-MSV/MLV complex (Mo-MSV=Moloney murine sarcoma virus; MLV=murine leukemia virus)) activity was investigated. Both compounds were found to inhibit moderately the focus formation of Mo-MSV/MLV complex in NIH3T3 cells (compound 4, IC₅₀=1.8 μM; compound 6, IC₅₀= 1.0 μM).