Structure activity relationships of fused bicyclic and urea derivatives of spirocyclic compounds as potent CCR1 antagonists |
| |
| Institution: | 1. Department of Medicinal Chemistry, Respiratory, Inflammation and Autoimmunity Innovative Medicines, AstraZeneca R&D, Pepparedsleden 1, SE-431 83 Mölndal, Sweden;2. Department of Medicinal Chemistry, AstraZeneca R&D Lund, Scheelevägen 1, SE-221 87 Lund, Sweden;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. Laboratory of Bio-Organic Chemistry, Department of Biochemistry and Biotechnology, University of Thessaly, 26 Ploutonos Str., 41221 Larissa, Greece;2. Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, Greece;3. Department of Physics, University of Cyprus, Nicosia, Cyprus;4. Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK;5. Centre for Materials Science, Division of Chemistry, University of Central Lancashire, Preston PR1 2HE, UK;1. Center for Integrated Molecular Brain Imaging, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark;2. Neurobiology Research Unit, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark;3. Dipartimento di Farmacia – Scienze del Farmaco, Università degli Studi di Bari A. Moro, Via Orabona, 4, 70125 Bari, Italy;4. PET and Cyclotron Unit, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark;1. Vertex Pharmaceuticals Incorporated, 50 Northern Avenue, Boston, MA 02210, USA;2. Vertex Pharmaceuticals Canada Incorporated, 275 Boul. Armand-Frappier, Laval, QC H7V 4A7, Canada;1. Enamine Ltd, 78 Chervonotkatska, Kyiv 02094, Ukraine;2. Institute of Bioorganic Chemistry and Petrochemistry, National Ukrainian Academy of Science, 1 Murmanska, Kyiv 02660, Ukraine;3. Taras Shevchenko National University, 62 Volodymyrska, Kyiv 01033, Ukraine;4. Institute of Chemistry, St. Petersburg State University, 26 Universitetskyi Prospekt, Peterhof 198504, Russian Federation |
| |
| Abstract: | A series of fused bicyclic and urea derivatives of spirocyclic compounds were designed, synthesised and evaluated in vitro as potent CCR1 antagonists. In particular, 4 (7 nM), 44 (1.3 nM), 48 (0.89 nM) and 50 (0.63 nM) were the most potent hCCR1 antagonists in this series of compounds. Moreover, some of these substances demonstrated good rodent cross-over, especially 46 which exhibited very high rat CCR1 binding affinity with an IC50 value of 16 nM. |
| |
| Keywords: | Chemokines Antagonists CCR1 Spirocyclic Receptor |
| 本文献已被 ScienceDirect 等数据库收录！ |
|
