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Improved P1/P1' substituents for cyclic urea based HIV-1 protease inhibitors: synthesis, structure-activity relationship, and X-ray crystal structure analysis.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 1997 May 09; Vol. 40 (10), pp. 1465-74. - Publication Year :
- 1997
-
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 microg/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 A 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.
- Subjects :
- Animals
Anti-HIV Agents chemical synthesis
Anti-HIV Agents chemistry
Anti-HIV Agents pharmacokinetics
Anti-HIV Agents pharmacology
Biological Availability
Cell Line
Crystallography, X-Ray
Dogs
HIV Protease Inhibitors chemical synthesis
HIV Protease Inhibitors pharmacokinetics
HIV Protease Inhibitors pharmacology
Humans
Magnetic Resonance Spectroscopy
Mass Spectrometry
Structure-Activity Relationship
HIV Protease Inhibitors chemistry
Urea analogs & derivatives
Subjects
Details
- Language :
- English
- ISSN :
- 0022-2623
- Volume :
- 40
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 9154969
- Full Text :
- https://doi.org/10.1021/jm960839i