Improved P1/P1‘ Substituents for Cyclic Urea Based HIV-1 Protease Inhibitors:  Synthesis, Structure−Activity Relationship, and X-ray Crystal Structure Analysis

We present several novel P1/P1‘ substituents that can replace the characteristic benzyl P1/P1‘ moiety of the cyclic urea based HIV protease inhibitor series. These substituents typically provide 5−10-fold improvements in binding affinity compared to the unsubstituted benzyl analogs. The best substituent was the 3,4-(ethylenedioxy)benzyl group. Proper balancing of the molecule's lipophilicity facilitated the transfer of this improved binding affinity into a superior cellular antiviral activity profile. Several analogs were evaluated further for protein binding and resistance liabilities. Compound <BO>18</BO> (IC<INF>90</INF> = 8.7 nM) was chosen for oral bioavailability studies based on its log P and solubility profile. A 10 mg/kg dose in dogs provided modest bioavailability with C<INF>max</INF> = 0.22 μg/mL. X-ray crystallographic analysis of two analogs revealed several interesting features responsible for the 3,4-(ethylenedioxy)benzyl-substituted analog's potency:  (1) Comparing the two complexes revealed two distinct binding modes for each P1/P1‘ substituent; (2) The ethylenedioxy moieties are within 3.6 Å of Pro 81 providing additional van der Waals contacts missing from the parent structure; (3) The enzyme's Arg 8 side chain moves away from the P1 substituent to accommodate the increased steric volume while maintaining a favorable hydrogen bond distance between the para oxygen substituent and the guanidine NH.