Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 60, Issue 10, Pages 4267-4278Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.7b00172
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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
- Ministry of Health, Welfare, and Labor of Japan
- Grants-in-Aid for Scientific Research [17K15710] Funding Source: KAKEN
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Design, synthesis, and evaluation of a new class of exceptionally potent HIV-1 protease inhibitors are reported. Inhibitor 5 displayed superior antiviral activity and drug-resistance profiles. In fact, this inhibitor showed several orders of magnitude improved antiviral activity over the FDA approved drug darunavir. This inhibitor incorporates an unprecedented 6-5-5 ring-fused crown-like tetrahydro-pyranofuran as the P2 ligand and an aminobenzothiazole as the P2' ligand with the (R)-hydroxyethylsulfonarnide isostere. The crown-like P2 ligand for this inhibitor has been synthesized efficiently-in an optically active form using a chiral Diels-Alder catalyst providing a key intermediate in high enantiomeric purity. Two high resolution X-ray structures of inhibitor-bound HIV-1 protease revealed extensive interactions with the backbone atoms of HIV-1 protease and provided molecular insight into the binding properties of these new inhibitors.
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