Discovery of 1,8-naphthyridin-2-one derivative as a potent and selective sphingomyelin synthase 2 inhibitor |
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| Institution: | 1. Department of Pharmacy, Health and Nutritional Sciences, DoE 2018-2022, University of Calabria, Edificio Polifunzionale, 87036 Rende (CS), Italy;2. Department of Biotechnology, Chemistry and Pharmacy, DoE 2018-2022, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy;3. Department of Life Sciences, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy;1. Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education and Yunnan Province, School of Chemical Science and Technology, Yunnan University, Kunming 650091, China;2. Key Laboratory of Bioactive Peptides of Yunnan Province/Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China;1. School of Pharmacy, Lanzhou University, Lanzhou 730000, PR China;2. Department of Medicinal, The Second Clinical Medical College of Northwest Minzu University & The Second Provincial People’s Hospital of Gansu Province, Lanzhou 730000, PR China;1. College of Pharmacy, College of Basic Medical Science, Dalian Medical University, Dalian 116044, PR China;2. Department of Hematology, Institute of Respiratory Diseases, the First Affiliated Hospital of Dalian Medical University, Dalian 116011, PR China;3. Dalian Buyun Biological Technology Co., Ltd., 116085, PR China |
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| Abstract: | Sphingomyelin synthase 2 (SMS2) has attracted attention as a drug target for the treatment of various cardiovascular and metabolic diseases. The modification of a high throughput screening hit, 2-quinolone 10, enhanced SMS2 inhibition at nanomolar concentrations with good selectivity against SMS1. To improve the pharmaceutical properties such as passive membrane permeability and aqueous solubility, adjustment of lipophilicity was attempted and 1,8-naphthyridin-2-one 37 was identified as a potent and selective SMS2 inhibitor. A significant reduction in hepatic sphingomyelin levels following repeated treatment in mice suggested that compound 37 could be an effective in vivo tool for clarifying the role of SMS2 enzyme and developing the treatment for SMS2-related diseases. |
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| Keywords: | Sphingomyelin synthase 2 SMS2 2-quinolone 1 8-naphthyridin-2-one |
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