Discovery of indane propanamides as potent and selective TRPV1 antagonists |
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| Affiliation: | 1. Laboratory of Medicinal Chemistry, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea;2. Medifron DBT, Ansan-City, Gyeonggi-Do 15426, Republic of Korea;3. Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892-4255, USA;4. Grünenthal Innovation, Grünenthal GmbH, D-52078 Aachen, Germany;1. Laboratory of Medicinal Chemistry, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea;2. National Leading Research Laboratory of Molecular Modeling & Drug Design, College of Pharmacy, Graduate School of Pharmaceutical Sciences, and Global Top 5 Research Program, Ewha Womans University, Seoul 120-750, Republic of Korea;3. Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA;4. Grünenthal Innovation, Grünenthal GmbH, D-52078 Aachen, Germany;1. Laboratory of Medicinal Chemistry, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea;2. Shenyang Pharmaceutical University, Shenyang 110016, China;3. Hainan Institute of Materia Medica, Haikou 570311, China;4. National Leading Research Laboratory of Molecular Modeling & Drug Design, College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 120-750, Republic of Korea;5. Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA;1. Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea;2. Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China;3. National Leading Research Lab of Molecular Modeling & Drug Design, College of Pharmacy, Graduate School of Pharmaceutical Sciences and Global Top 5 Research Program, Ewha Womans University, Seoul 120-750, Republic of Korea;4. Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA;1. Institute for Innovative Drug Design and Evaluation, School of Pharmacy, Henan University, N. Jinming Ave., Kaifeng, Henan, 475004, China;2. State Key Laboratory of Natural Medicines, Center of Drug Discovery, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, Jiangsu, 210009, China;3. School of Pharmaceutical Sciences, South-Central University for Nationalities, 182 Minyuan Road, Wuhan, Hubei, 430074, China;1. Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, China;2. School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China;3. Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA;4. The Brain Science Center, Beijing Institute of Basic Medical Sciences, Beijing 100850, China |
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| Abstract: | A series of indane-type acetamide and propanamide analogues were investigated as TRPV1 antagonists. The analysis of structure–activity relationship indicated that indane A-region analogues exhibited better antagonism than did the corresponding 2,3-dihydrobenzofuran and 1,3-benzodioxole surrogates. Among them, antagonist 36 exhibited potent and selective antagonism toward capsaicin for hTRPV1 and mTRPV1. Further, in vivo studies indicated that antagonist 36 showed excellent analgesic activity in both phases of the formalin mouse pain model and inhibited the pain behavior completely at a dose of 1 mg/kg in the 2nd phase. |
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| Keywords: | Vanilloid receptor 1 TRPV1 antagonist Analgesic |
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