Design and synthesis of spirocyclic compounds as HCV replication inhibitors by targeting viral NS4B protein |
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| Affiliation: | 1. GlaxoSmithKline, Antiviral Discovery Performance Unit, 5 Moore Drive, Research Triangle Park, NC 27709, USA;2. GlaxoSmithKline, Platform Technology and Science, 5 Moore Drive, Research Triangle Park, NC 27709, USA;3. GlaxoSmithKline, Anti Bacterial Discovery Performance Unit, 5 Moore Drive, Research Triangle Park, NC 27709, USA;1. Department of Medicinal Chemistry, Merck & Co., 33 Avenue Louis Pasteur, Boston, MA 02115, USA;2. Department of Structural Chemistry, Merck & Co., 33 Avenue Louis Pasteur, Boston, MA 02115, USA;3. Department of In Vitro Sciences, Merck & Co., 33 Avenue Louis Pasteur, Boston, MA 02115, USA;4. Department of Pharmacology, Merck & Co., 33 Avenue Louis Pasteur, Boston, MA 02115, USA;5. Department of Drug Metabolism, Merck & Co., 33 Avenue Louis Pasteur, Boston, MA 02115, USA;6. Department of Basic Pharmaceutical Sciences, Merck & Co., 33 Avenue Louis Pasteur, Boston, MA 02115, USA;7. Department of Oncology, Merck & Co., 33 Avenue Louis Pasteur, Boston, MA 02115, USA;1. Boehringer Ingelheim Pharma GmbH & Co. KG, Department of Medicinal Chemistry, Birkendorfer Str. 65, 88397 Biberach an der Riss, Germany;2. Boehringer Ingelheim Pharma GmbH & Co. KG, Department of Cardiometabolic Research, Birkendorfer Str. 65, 88397 Biberach an der Riss, Germany;3. Boehringer Ingelheim Pharma GmbH & Co. KG, Department of Drug Discovery Support Research Germany, Birkendorfer Str. 65, 88397 Biberach an der Riss, Germany;1. Academy of Scientific and Innovative Research (AcSIR), India;2. CSIR-Indian Institute of Integrative Medicine, Jammu, J & K, 180001, India;3. CSIR-Central Drug Research Institute, Lucknow, 226031, India;1. Beijing Institute of Pharmacology & Toxicology, 27 Tai-Ping Road, Beijing 100850, China;2. Duke University Medical Center, Box 2926, Surgical Oncology Research Facility, Durham, NC 27710, USA;3. Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA;4. Chinese Medicine Research and Development Center, China Medical University and Hospital, Taichung, Taiwan;1. Biota Europe Ltd, Begbroke Science Park, Oxfordshire OX5 1PF, United Kingdom;2. Biota Scientific Management Pty Ltd, 10/585 Blackburn Road, Notting Hill, VIC 3168, Australia;3. Jubilant Chemsys Ltd, B-34, Sector-58, Noida 201301, India;1. Lead Identification and Optimization Support, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, D-88397 Biberach a.d. Riss, Germany;2. Medicinal Chemistry, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, D-88397 Biberach a.d. Riss, Germany;3. Drug Discovery Support, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, D-88397 Biberach a.d. Riss, Germany;4. Respiratory Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, D-88397 Biberach a.d. Riss, Germany |
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| Abstract: | Two novel series of spirocyclic piperidine analogs appended to a pyrazolo[1,5-a]pyridine core were designed, synthesized and evaluated for their anti-HCV activity. A series of piperidine ketals afforded dispiro 6p which showed excellent in vitro anti-HCV activities (EC50 of 1.5 nM and 1.2 nM against genotype 1a and 1b replicons, respectively). A series of piperidine oxazolidinones afforded 27c which showed EC50’s of 10.9 nM and 6.1 nM against 1a and 1b replicons, respectively. Both compounds 6p and 27c bound directly to non-structural NS4B protein in vitro (IC50’s = 10.2 and 30.4 nM, respectively) and exhibited reduced potency in replicons containing resistance mutations encoding changes in the NS4B protein. |
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| Keywords: | NS4B Hepatitis C virus (HCV) Replication inhibitors Spirocyclic ketals |
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