Structure-based amelioration of PXR transactivation in a novel series of macrocyclic allosteric inhibitors of HIV-1 integrase |
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| Affiliation: | 1. Computer-Aided Drug Design, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA;2. Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA;3. Molecular Structure & Design, Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543-4000, USA;4. Protein Sciences, Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543-4000, USA;5. Lead Discovery and Optimization, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA;6. Virology Discovery Biology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA;7. Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA;1. Department of Ultrasound Diagnosis, Xijing Hospital, Fourth Military Medical University, Xi''an 710038, China;2. Department of Pharmaceutics, School of Pharmacy, Fourth Military Medical University, Xi’an 710032, China;1. Neuroscience Discovery Chemistry, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT 06492, United States;2. Process Research and Development, Bristol-Myers Squibb, 1 Squibb Drive, New Brunswick, NJ 08903, United States;3. Neuroscience Discovery Biology, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT 06492, United States;4. Department of Metabolism and Pharmcokinetics, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT 06492, United States;5. Department of Toxicology, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT 06492, United States;1. Department of Human Anatomy, School of Medicine, Jinan University, Guangzhou 510632, China;2. College of Materials and Energy, South China Agricultural University, Guangzhou 510642, China;3. Department of Ophthalmology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China;4. School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China;1. Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Ji’nan 250012, China;2. Duke University Medical Center, Box 2926, SORF, Durham, NC 27710, United States;3. Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599-7568, United States;4. Chinese Medicine Research and Development Center, China Medical University and Hospital, Taichung 40402, Taiwan, China;5. Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, K.U.Leuven, Herestraat 49 Postbus 1043 (09.A097), B-3000 Leuven, Belgium;1. Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India;2. Academy of Scientific & Innovative Research (AcSIR), CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India;3. Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India;1. Department of Chemical Biology & Therapeutics, St. Jude Children''s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA;2. Integrated Biomedical Sciences Program, University of Tennessee Health Science Center, 920 Madison Avenue, Memphis, TN 38163, USA;3. School of Pharmacy, University of Pittsburgh, 3501 Terrace Street, Pittsburgh, PA 15213, USA;4. Department of Molecular Medicine, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA |
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| Abstract: | Previous studies have identified a series of imidazo[1,2-a]pyridine (IZP) derivatives as potent allosteric inhibitors of HIV-1 integrase (ALLINIs) and virus infection in cell culture. However, IZPs were also found to be relatively potent activators of the pregnane-X receptor (PXR), raising the specter of induction of CYP-mediated drug disposition pathways. In an attempt to modify PXR activity without affecting anti-HIV-1 activity, rational structure-based design and modeling approaches were used. An X-ray cocrystal structure of (S,S)-1 in the PXR ligand binding domain (LBD) allowed an examination of the potential of rational structural modifications designed to abrogate PXR. The introduction of bulky basic amines at the C-8 position provided macrocyclic IZP derivatives that displayed potent HIV-1 inhibitory activity in cell culture with no detectable PXR transactivation at the highest concentration tested. |
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| Keywords: | PXR ALLINI HIV-1 integrase LEDGF/p75 Macrocycle Inhibitor |
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