Discovery of novel tetrahydroisoquinoline-containing pyrimidines as ALK inhibitors |
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| Affiliation: | 1. Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 305-600, Republic of Korea;2. Department of Medicinal Chemistry and Pharmacology, University of Science & Technology, Daejeon 305-550, Republic of Korea;3. College of Pharmacy, Chungnam National University, Daejeon 305-764, Republic of Korea;1. Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases & Department of Medicinal Chemistry, College of Pharmaceutical Sciences, Soochow University, 199 Ren’ai Road, Suzhou 215123, China;2. Department of Pharmacy, Suzhou Vocational Health College, 28 Kehua Road, Suzhou 215009, China;3. College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY 40536, USA;4. Central Research Institute of Shanghai Pharmaceuticals Holding Co., Ltd, Tower 4, No. 898 Ha Lei Road, Pudong New District, Shanghai 201203, China;1. Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences, Lavrentyev Avenue 9, 630090 Novosibirsk, Russia;2. Novosibirsk State University, Pirogova St. 1, Novosibirsk 630090, Russia;3. Institute of Molecular Biology and Biophysics, Timakova St. 2/12, Novosibirsk 630117, Russia;1. Microbiology, Bioorganic and Macromolecular Chemistry, Faculty of Pharmacy, Université libre de Bruxelles, Boulevard du Triomphe, 1050 Brussels, Belgium;2. Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA;1. Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA;2. Department of Oncology, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA;3. Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA;4. Department of Molecular Structure, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA;5. Department of Molecular Structure, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA;6. Department of High-Throughput Screening/Molecular Pharmacology, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA;7. Department of High-Throughput Screening/Molecular Pharmacology, Amgen Inc., 360 Binney Street, Cambridge, MA 02142, USA;8. Department of Basic Pharmaceutics, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA |
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| Abstract: | Exploration of the two-position side chain of pyrimidine in LDK378 with tetrahydroisoquinolines (THIQs) led to discovery of 8 and 17 as highly potent ALK inhibitors. THIQs 8 and 17 showed encouraging in vitro and in vivo xenograft efficacies, comparable with those of LDK378. Although THIQ analogs (8a–o and 17a–i) prepared were not as active as their parent compounds, both 8 and 17 have significant inhibitory activities against various ALK mutant enzymes including G1202R, indicating that this series of compounds could be further optimized as useful ALK inhibitors overcoming the resistance issues found from crizotinib and LDK378. |
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| Keywords: | ALK Cancer NSCLC LDK378 Tetrahydroisoquinoline (THIQ) |
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