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 char acteristic benzyl P1/P1' moiety of the cyclic urea based HIV protease inhibitor series. These substituents typically provide 5-10-fold impro vements in binding affinity compared to the unsubstituted benzyl analo gs. The best substituent was the 3,4-(ethylenedioxy)benzyl group. Prop er balancing of the molecule's lipophilicity facilitated the transfer of this improved binding affinity into a superior cellular antiviral a ctivity profile. Several analogs were evaluated further for protein bi nding and resistance liabilities. Compound 18 (IC90 = 8.7 nM) was chos en for oral bioavailability studies based on its log P and solubility profile. A 10 mg/kg dose in dogs provided modest bioavailability with C-max = 0.22 mu g/mL. X-ray crystallographic analysis of two analogs r evealed several interesting features responsible for the 3,4-(ethylene dioxy)benzyl-substituted analog's potency: (1) Comparing the two compl exes revealed two distinct binding modes for each P1/P1' substituent; (2) The ethylenedioxy moieties are within 3.6 Angstrom of Pro 81 provi ding additional van der Waals contacts missing from the parent structu re; (3) The enzyme's Arg 8 side chain moves away from the P1 substitue nt to accommodate the increased steric volume while maintaining a favo rable hydrogen bond distance between the para oxygen substituent and t he guanidine NH.