Discovery of thieno[2,3-d]pyrimidin-4(3H)-one derivatives as a new class of ROCK inhibitors |
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| Institution: | 1. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China;2. Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, China;1. Reata Pharmaceuticals, Inc., 2801 Gateway Drive, Suite 150, Irving, TX 75063, USA;2. Department of Chemistry, Michigan State University, 578 South Shaw Lane, East Lansing, MI 48824, USA;1. Pharmaceutical Chemistry Department, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt;2. Department of Food Sciences, The University of Otago, Dunedin, New Zealand;3. Department of Clinical Pharmacology, Faculty of Medicine, Alexandria University, Alexandria, Egypt;4. Pharmaceutical Chemistry Department, Faculty of Pharmacy, Kafrelsheikh University, Kafr El-Sheikh 33516, Egypt;1. Institute of Molecular Biology and Genetics NAS of Ukraine, 150 Akademika Zabolotnogo Str., Kyiv 03680, Ukraine;2. Otava Ltd, 65 400 Applewood Crescent, Unit 100, Vaughan, Ontario L4K 0C3, Canada;1. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, People’s Republic of China;2. Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, 610041, People’s Republic of China |
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| Abstract: | Herein, we report the discovery of a series of thieno2,3-d]pyrimidin-4(3H)-one derivatives as a new class of ROCK inhibitors. Structure-activity relationship studies of these compounds led to the identification of the most potent compound, 3-(3-methoxybenzyl)-6-(1H-pyrrolo2,3-b]pyridin-4-yl)thieno2,3-d]pyrimidin-4(3H)-one (8k), which showed IC50 values of 0.004 μM and 0.001 μM against ROCK Ⅰ and ROCK Ⅱ, respectively. In vitro, 8k significantly reduced the phosphorylation level of ROCK downstream signaling protein and induce changes in cell morphology and migration. Overall, this study provides a promising lead compound for drug discovery targeting ROCKs. |
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| Keywords: | ROCKs Kinase inhibitor Structure-activity relationship Cell migration Cell morphology |
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