Novel potent and selective pyrazolylpyrimidine-based SYK inhibitors |
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| Institution: | 1. R&D Oncology, AstraZeneca, Cambridge, United Kingdom;2. R&D Oncology, AstraZeneca, Boston, MA, United States;3. Discovery Sciences, AstraZeneca, Cambridge, United Kingdom;4. Pharmaron Beijing Co., Ltd., 6 Taihe Road BDA, Beijing 100176, PR China;1. School of Chemistry and Physics, University of KwaZulu-Natal, P/Bag X54001, Westville, Durban, South Africa;2. Department of Pharmacology, Penn State Cancer Institute, CH72, Penn State College of Medicine, 500 University Drive, Hershey, PA 17033, USA;1. Department of Radiology, Washington University School of Medicine, 510 South Kingshighway Boulevard, St. Louis, MO 63110, United States;2. Department of Anesthesiology, Center for the Study of Itch and Sensory Disorders, Washington University School of Medicine, St. Louis, MO 63110, United States;1. Department of Human Anatomy, School of Medicine, Jinan University, Guangzhou 510632, China;2. College of Materials and Energy, South China Agricultural University, Guangzhou 510642, China;3. Department of Ophthalmology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China;4. School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China;1. Natural Product Research Center, Korea Institute of Science and Technology (KIST), Gangneung 25451, Republic of Korea;2. Convergent Research Center for Diagnosis, Treatment, and Care System of Dementia, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea;3. Natural Product Informatics Research Center, Korea Institute of Science and Technology (KIST), Gangneung 25451, Republic of Korea;4. Department of Biotechnology, Vietnam-Korea Institute of Science and Technology (VKIST), Hanoi, Viet Nam;5. Institute of Food Industrialization, Institutes of Green Bio Science & Technology and Graduate School of International Agricultural Technology, Seoul National University, Pyeongchang-gun, Gangwon-do 25354, Republic of Korea;6. Department of Anatomy, College of Dentistry, Gangnueng Wonju National University (GWNU), Gangneung 25457, Republic of Korea;7. Department of Biochemistry and Molecular Biology, College of Dentistry, Gangneung Wonju National University (GWNU), Gangneung 25457, Republic of Korea;8. Division of Bio-Medical Science and Technology, University of Science and Technology (UST), Daejun 34113, Republic of Korea;1. Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI 48105, USA;2. Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109, USA;3. Vahlteich Medicinal Chemistry Core, University of Michigan, Ann Arbor, MI 48109, USA;4. Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI 48109, USA;5. Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA;1. Graduate School of Science, Osaka Prefecture University, Osaka 599-8531, Japan;2. Whol Institute for Drug Discovery of the Nancy and Stephen Grand Israel National Center for Personalized Medicine, The Weizmann Institute of Science, Rehovot 7610001, Israel;3. Department of Organic Chemistry, The Weizmann Institute of Science, Rehovot 76100, Israel |
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| Abstract: | Hybridisation of amino-pyrimidine based SYK inhibitors (e.g. 1a) with previously reported diamine-based SYK inhibitors (e.g. TAK-659) led to the identification and optimisation of a novel pyrimidine-based series of potent and selective SYK inhibitors, where the original aminomethylene group was replaced by a 3,4-diaminotetrahydropyran group. The initial compound 5 achieved excellent SYK potency. However, it suffered from poor permeability and modest kinase selectivity. Further modifications of the 3,4-diaminotetrahydropyran group were identified and the interactions of those groups with Asp512 were characterised by protein X-ray crystallography. Further optimisation of this series saw mixed results where permeability and kinase selectivity were increased and oral bioavailability was achieved in the series, but at the expense of potent hERG inhibition. |
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| Keywords: | SYK Diamine Kinase selectivity |
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