Design,synthesis and preliminary biological evaluation of 4-aminopyrazole derivatives as novel and potent JAKs inhibitors |
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| Affiliation: | 1. Department of Medicinal Chemistry, School of Pharmacy, Shandong University, Ji’nan, Shandong 250012, PR China;2. Georgia Research Alliance Eminent Scholar in Drug Discovery, Department of Chemistry, Georgia State University, United States;1. School of Pharmacy, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway, Selangor Darul Ehsan 47500, Malaysia;2. School of Pharmacy, Curtin Health Innovation Research Institute, Faculty of Health Sciences, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia;1. School of Pharmacy, Curtin Health Innovation Research Institute, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia;2. School of Pharmacy, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway, Selangor Darul Ehsan 47500, Malaysia;1. Department of Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA;2. Department of Biochemical and Cellular Pharmacology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA;3. Department of Translational Immunology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA;4. Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA;5. Department of Structural Biology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA;6. Department of Immunology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA;7. Department of Small Molecule Pharmaceutical Sciences, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA;8. ChemPartner Co. Ltd., 998 Halei Road, Zhangjiang Hi-Tech Park, Shanghai 201203, PR China;9. Argenta Discovery Services, CRL, 8-9 Spire Green Centre, Harlow, Essex CM19 5TR, United Kingdom;1. Postovsky Institute of Organic Synthesis of the Ural Branch of the Russian Academy of Science, S. Kovalevskoi St., 22, Ekaterinburg, 620108, Russia;2. Ural Federal University Named After the First President of Russia B.N. Yeltsin, Mira St. 19, Ekaterinburg, 620002, Russia;3. Perm National Research Polytechnic University, Komsomolsky Av., 29, Perm, 614990, Russia;4. Ural Research Institute for Dermatology, Venereology and Immunopathology, Shcherbakova St., 8, Ekaterinburg, 620076, Russia;5. Institute of Physiologically Active Compounds of the Russian Academy of Sciences, Severny Proezd 1, Chernogolovka, 142432, Russia;6. Ufa Institute of Chemistry of Russian Academy of Science, Octyabrya Av., 71, Ufa, 450078, Russia;1. Small Molecule Research, Pharma Research & Early Development, pRED, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, United States;2. Roche Palo Alto, 3401 Hillview Ave, Palo Alto, CA 94304, United States |
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| Abstract: | JAKs inhibitors were widely applied in the treatment of immunodeficiency diseases, inflammation and cancers. We designed and synthesized a novel series of 4-aminopyrazole derivatives, which showed inhibitory potency against various JAKs. The in vitro protein kinase inhibition experiment indicated that compounds 17k, 17l, 17m and 17n could inhibit JAKs effectively. Among them, compound 17m possessed the highest protein kinase inhibitory rates (%) at 10 μM, which were 97, 96 and 100 to JAK1, JAK2 and JAK3, respectively. Further evaluation revealed that the IC50 values of 17m against JAK1, JAK2 and JAK3 were 0.67 μM, 0.098 μM and 0.039 μM, respectively. Moreover, western blotting results showed compound 17m could inhibit the phosphorylation of JAK2 in Hela cells effectively. The data supports the further investigation of these compounds as novel JAKs inhibitors. |
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| Keywords: | Inhibitors JAKs Kinase 4-Aminopyrazole |
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