Discovery of Potent, Selective, and Brain-Penetrant 1H-Pyrazol-5-yl-1H-pyrrolo[2,3-b]pyridines as Anaplastic Lymphoma Kinase (ALK) Inhibitors
| Autor: | Imamura Keisuke, Tomoaki Hasui, Y. Hiura, Kumar Singh Saikatendu, Ikuo Fujimori, Morio Murakami, Takeshi Wakabayashi, Tsuyoshi Ishii, Hua Zou, J.D. Lawson, S.W. Lane, Y. Kikko, Masaomi Miyamoto, Hiroshi Imoto, A. Nakatani, M. Kasahara, Youichi Kawakita, Takeshi Kato, Makoto Fushimi |
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| Rok vydání: | 2019 |
| Předmět: |
Swine
medicine.drug_class Central nervous system Plasma protein binding Crystallography X-Ray 01 natural sciences Receptor tyrosine kinase Inhibitory Concentration 50 Mice Structure-Activity Relationship 03 medical and health sciences hemic and lymphatic diseases Drug Discovery medicine Animals Humans Structure–activity relationship Anaplastic lymphoma kinase Anaplastic Lymphoma Kinase Phosphorylation Protein Kinase Inhibitors 030304 developmental biology Mice Inbred ICR 0303 health sciences Molecular Structure biology Chemistry HEK 293 cells Brain Biological Transport 0104 chemical sciences ALK inhibitor 010404 medicinal & biomolecular chemistry HEK293 Cells medicine.anatomical_structure biology.protein Cancer research LLC-PK1 Cells Molecular Medicine |
| Zdroj: | Journal of Medicinal Chemistry. 62:4915-4935 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | Anaplastic lymphoma kinase (ALK), a member of the receptor tyrosine kinase family, is predominantly expressed in the brain and implicated in neuronal development and cognition. However, the detailed function of ALK in the central nervous system (CNS) is still unclear. To elucidate the role of ALK in the CNS, it was necessary to discover a potent, selective, and brain-penetrant ALK inhibitor. Scaffold hopping and lead optimization of N-(2,4-difluorobenzyl)-3-(1 H-pyrazol-5-yl)imidazo[1,2- b]pyridazin-6-amine 1 guided by a cocrystal structure of compound 1 bound to ALK resulted in the identification of (6-(1-(5-fluoropyridin-2-yl)ethoxy)-1-(5-methyl-1 H-pyrazol-3-yl)-1 H-pyrrolo[2,3- b]pyridin-3-yl)((2 S)-2-methylmorpholin-4-yl)methanone 13 as a highly potent, selective, and brain-penetrable compound. Intraperitoneal administration of compound 13 significantly decreased the phosphorylated-ALK (p-ALK) levels in the hippocampus and prefrontal cortex in the mouse brain. These results suggest that compound 13 could serve as a useful chemical probe to elucidate the mechanism of ALK-mediated brain functions and the therapeutic potential of ALK inhibition. |
| Databáze: | OpenAIRE |
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