Discovery of functionalized bisimidazoles bearing cyclic aliphatic-phenyl motifs as HCV NS5A inhibitors |
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| Institution: | 1. Discovery Chemistry, Erl Wood Manor, Lilly Research Laboratories, A Division of Eli Lilly and Company, Sunningdale Road, Windlesham, Surrey GU20 6PH, UK;2. Discovery Chemistry, Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA;3. Neuroscience Discovery, Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA;4. Musculoskeletal Research, Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA;1. Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Corrensstraße 40, D-48149 Münster, Germany;2. Klinik für Nuklearmedizin, Universitätsklinikum Münster, Albert-Schweitzer-Campus 1, D-48149 Münster, Germany;3. European Institute for Molecular Imaging, Westfälische Wilhelms-Universität Münster, Waldeyerstraße 15, D-48149 Münster, Germany;4. Cells-in-Motion Cluster of Excellence (EXC 1003-CiM), University of Münster, Waldeyerstraße 15, D-48149 Münster, Germany;1. Institute of Drug Synthesis and Pharmaceutical Process, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China;2. Shaanxi Key Laboratory of Phytochemistry, College of Chemistry, Baoji University of Arts & Sciences, Baoji, 721013 Shaanxi, PR China;1. Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand;2. Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612, USA;3. Global Alliance for TB Drug Development, 40 Wall St, New York 10005, USA;1. Department of Medicinal Chemistry, School of Pharmacy, Health Science Center, Xi''an Jiaotong University, No 76, Yanta West Road, Xi''an 710061, PR China;2. Jiangsu Simcere Pharmaceutical Co. Ltd., No 699-18, Xuan Wu District, Nanjing 210042, PR China;1. Université de Nantes, Nantes Atlantique Universités, Laboratoire de Chimie Thérapeutique, Cibles et Médicaments des Infections et du Cancer, IICiMed UPRES EA 1155, UFR de Sciences Pharmaceutiques et Biologiques, 1 rue Gaston Veil, 44035 Nantes, France;2. UMR 892 INSERM/6299 CNRS/Université de Nantes, Team 8 ‘Cell Survival and Tumor Escape in Breast Cancer’, Institut de Recherche Thérapeutique de l''Université de Nantes, 8 quai Moncousu, BP 70721, 44007 Nantes Cedex 1, France |
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| Abstract: | This Letter describes the discovery of a number of functionalized bisimidazoles bearing a cyclohexylphenyl, piperidylphenyl, or bicyclo2,2,2]octylphenyl motif as HCV NS5A inhibitors. Compounds 2c, 4b and 6 have demonstrated low single-digit nM potency in gt-1a replicon and double-digit pM potency in gt-1b replicon, respectively. Moreover, both 4b and 6 have, respectively, exhibited good oral bioavailability in rats with a favorable liver/plasma ratio of the drug concentration. |
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| Keywords: | HCV NS5A inhibitor Bisimidazole |
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