Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 58, Issue 13, Pages 5334-5343Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.5b00676
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Funding
- National Institutes of Health [GM53386, GM62920]
- U.S. Department of Energy, Basic Energy Sciences, Office of Science [W-31-109-Eng-38]
- Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health
- Ministry of Education, Culture, Sports, Science, and Technology of Japan (Monbu Kagakusho)
- Ministry of Health, Welfare, and Labor of Japan
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We report the design, synthesis, X-ray structural studies, and biological evaluation of a novel series of HIV-1 protease inhibitors. We designed a variety of functionalized biphenyl derivatives to make enhanced van der Waals interactions in the Si subsite of HIV-1 protease. These biphenyl derivatives were conveniently synthesized using a Suzuki-Miyaura cross-coupling reaction as the key step. We examined the potential of these functionalized biphenyl-derived P1 ligands in combination with 3-(S)-tetrahydrofuranyl urethane and bis-tetrahydrofuranyl urethane as the P2 ligands. Inhibitor 21e, with a 2-methoxy-1,1'-biphenyl derivative as P1 ligand and bis-THF as the P2 ligand, displayed the most potent enzyme inhibitory and antiviral activity. This inhibitor also exhibited potent activity against a panel of multidrug-resistant HIV-1 variants. A high resolution X-ray crystal structure of related Boc-derivative 17a-bound HIV-1 protease provided important molecular insight into the ligand-binding site interactions of the biphenyl core in the Si subsite of HIV-1 protease.
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