Discovery of nonpeptide 3,4-dihydroquinazoline-4-carboxamides as potent and selective sst2 agonists |
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| Institution: | 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. 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. Department of Radiology, Stanford University School of Medicine, Stanford, CA 94305, United States;2. Department of Theoretical Chemistry and Biology, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, S-106 91 Stockholm, Sweden |
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| Abstract: | Nonpeptide sst2 agonists can provide a new treatment option for patients with acromegaly, carcinoid tumors, and neuroendocrine tumors. Our medicinal chemistry efforts have led to the discovery of novel 3,4-dihydroquinazoline-4-carboxamides as sst2 agonists. This class of molecules exhibits excellent human sst2 potency and selectivity against sst1, sst3, sst4 and sst5 receptors. Leading compound 3-(3-chloro-5-methylphenyl)-6-(3-fluoro-2-hydroxyphenyl)-N,7-dimethyl-N-{(2S)-pyrrolidin-2-yl]methyl}-3,4-dihydroquinazoline-4-carboxamide (28) showed no inhibition of major CYP450 enzymes (2C9, 2C19, 2D6 and 3A4) and weak inhibition of the hERG channel. |
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| Keywords: | Somatostatin Sst2 agonist Acromegaly Neuroendocrine tumors 3 4-dihydroquinazoline-4-carboxamide |
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