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

Citations Over TimeTop 23% of 1997 papers

Abstract

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 18 (IC90 = 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 Cmax = 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.

Related Papers

• → Lipophilicity and antiproliferative activity profiling of 2-benzylidencycloalkanones(2007)12 cited
• → A New Straightforward Method for Lipophilicity (log<em>P</em>) Measurement using <sup>19</sup>F NMR Spectroscopy(2019)6 cited
• → The origin and nature of the π-electron steric effect(1977)2 cited
• → PSII Inhibitory Activity of 2,4-Diamino-6-chloro-s-triazines with a Chiralsec-Butyl and/or α-Methylbenzyl Group(1990)1 cited
• Prediction of Lipophilicity of Orthopramides by Comparative Molecular Field Analysis (CoMFA)(1995)