Functionalized triazines as potent HCV entry inhibitors |
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| Institution: | 1. Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States;2. Department of Virology Discovery Biology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States;3. Department of Computer-Assisted Drug Design, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States;4. Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States;5. Department of Lead Evaluation, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States;1. Takeda California, 10410 Science Center Drive, San Diego 92121, USA;2. Takeda Pharmaceutical Company, Ltd, 2-26-1, Muraokahigashi, Fujisawa, Kanagawa 251-855, Japan;1. Department of Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA;2. Department of Drug Metabolism, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA;3. Department of In Vitro Sciences, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA;4. Department of Neuroscience, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA;1. Lead Exploration Unit, Drug Discovery Initiative, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan;2. Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan;3. Drug Discovery Initiative, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan;1. Department of Discovery Chemistry, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA;2. Department of Chemistry, Modeling and Informatics, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA;3. Department of Pharmacokinetics, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA;4. Department of Immunology, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA;1. Cardiovascular and Metabolic Research, Janssen Research & Development, LLC, Welsh & McKean Roads, Box 776, Spring House, PA 19477, United States;2. CymaBay Therapeutics, Inc., 7999 Gateway Blvd, Newark, CA 94560, United States;1. Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492-7660, USA;2. One Squibb Drive, New Brunswick, NJ 08903, USA |
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| Abstract: | A series of potent and novel acylsulfonamide-bearing triazines were synthesized and the structure-activity relationships (SARs) as HCV entry inhibitors were evaluated. This acylsulfonamide series was derived from an early lead, 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid wherein the carboxylic acid was replaced with an acylsulfonamide moiety. This structural modification provided a class of compounds which projected an additional vector off the terminus of the acylsulfonamide functionality as a means to drive activity. This effort led to the discovery of potent analogues within this series that demonstrated sub-nanomolar EC50 values in the HCV pseudotype particle (HCVpp) assay. |
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| Keywords: | Hepatitis C virus Entry inhibitor Acyl sulfonamide Triazine |
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