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The discovery of potent and selective non-steroidal glucocorticoid receptor modulators,suitable for inhalation
Institution:1. Discovery Sciences, Innovative Medicines, AstraZeneca R&D, Pepparedsleden 1, SE-431 83 Mölndal, Sweden;2. AstraZeneca R&D Lund, Scheelevägen 1, SE-221 87 Lund, Sweden;3. Respiratory, Inflammation and Autoimmunity, Innovative Medicines, AstraZeneca R&D, Pepparedsleden 1, SE-431 83 Mölndal, Sweden;1. Zhejiang Province Key Laboratory of Anesthesiology, Department of Anesthesiology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China;2. School of Materials Science and Chemical Engineering, Ningbo University, Ningbo, China;3. College of Food and Pharmaceutical Sciences, Ningbo University, Ningbo, China;1. Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA;2. Albany Molecular Research, Inc., 26 Corporate Cir, Albany, NY 12212, USA;1. College of Life Science, Nanjing Normal University, No. 1 Wenyuan Road, Nanjing 210046, PR China;2. Jiangsu Chia Tai Fenghai Pharmaceutical Co. Ltd., No. 9 Weidi Road, Nanjing 210046, PR China;3. College of Science, Nanjing Forestry University, No. 159 Longpan Road, Nanjing 210037, PR China;1. Oncology R&D, AstraZeneca, Cambridge CB4 0WG, United Kingdom;2. Oncology R&D, AstraZeneca, 35 Gatehouse Drive, Waltham, MA 02451, United States;3. Discovery Sciences R&D, AstraZeneca, Cambridge CB4 0WG, United Kingdom;4. Discovery Sciences R&D, 35 Gatehouse Drive, Waltham, MA 02451, United States;1. Discovery Sciences, AstraZeneca, Mölndal, Pepparedsleden 1, 43183 Mölndal, Sweden;2. Joint BSC-CRG-IRB Research Program in Computational Biology, Barcelona Supercomputing Center, Jordi Girona 29, 08034 Barcelona, Spain;3. R&D Information, AstraZeneca, Pepparedsleden 1, 43183 Mölndal, Sweden;4. RIA, AstraZeneca, Pepparedsleden 1, 43183 Mölndal, Sweden;5. CVMD, AstraZeneca, Pepparedsleden 1, 43183 Mölndal, Sweden;6. Institució Catalana de Recerca i Estudis Avançats (ICREA), Passeig Lluís Companys 23, 08010 Barcelona, Spain
Abstract:We report the discovery of highly potent and selective non-steroidal glucocorticoid receptor modulators with PK properties suitable for inhalation. A high throughput screen of the AstraZeneca compound collection identified sulfonamide 3 as a potent non-steroidal glucocorticoid receptor ligand. Further optimization of this lead generated indazoles 30 and 48 that were progressed to characterization in in vivo models. X-ray crystallography was used to gain further insight into the binding mode of selected ligands.
Keywords:Glucocorticoid receptor  Non-steroidal selective glucocorticoid receptor modulators  Inhalation  Indazoles
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