Structural development of N-(4-phenoxyphenyl)benzamide derivatives as novel SPAK inhibitors blocking WNK kinase signaling |
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| Institution: | 1. Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University (TMDU), 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan;2. Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan;1. Department of Chemistry, Department of Immunology and Microbial Science, The Skaggs Institute for Chemical Biology, The Worm Institute of Research and Medicine (WIRM), The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, United States;2. Cessation Therapeutics LLC, 3031 Tisch Way Ste 505, San Jose, CA 95128, United States;1. College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China;2. Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Panum, Maersk Tower, Blegdamsvej 3B, 2200 Copenhagen N, Denmark;3. State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu 210009, China;1. Food and Pharmacy College, Zhejiang Ocean University, Zhejiang, Zhoushan 316022, PR China;2. Key Laboratory of Natural Resource of the Changbai Mountain and Functiaonal Molecules, Ministry of Education, Yanbian University, Jilin Yanji 133000, China;1. Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China;2. China Crop Protection Industry Association, Beijing 100723, China |
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| Abstract: | We report here structural development of N-(4-phenoxyphenyl)benzamide derivatives as novel SPAK (STE20/SPS1-related proline/alanine-rich kinase) inhibitors. Abnormal activation of the signal cascade of with-no-lysine kinase (WNK) with OSR1 (oxidative stress-responsive kinase 1)/SPAK and NCC (NaCl cotransporter) results in characteristic salt-sensitive hypertension, and therefore inhibitors of the WNK-OSR1/SPAK-NCC cascade are candidates for antihypertensive drugs. Based on the structure of lead compound 2, we examined the SAR of N-(4-phenoxyphenyl)benzamide derivatives, and developed compound 20l as a potent SPAK inhibitor. Compounds 20l is a promising candidate for a new class of antihypertensive drugs. |
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| Keywords: | Antihypertensive drugs SPAK WNK kinase signaling |
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