Discovery of Potent, Selective, and Brain-Penetrant 1 H-Pyrazol-5-yl-1 H-pyrrolo[2,3- b]pyridines as Anaplastic Lymphoma Kinase (ALK) Inhibitors.

Autor:	Fushimi M; Neuroscience Drug Discovery Unit, Research , Takeda Pharmaceutical Company Limited , 26-1, Muraoka-Higashi 2-chome, Fujisawa , Kanagawa 251-8555 , Japan., Fujimori I; Neuroscience Drug Discovery Unit, Research , Takeda Pharmaceutical Company Limited , 26-1, Muraoka-Higashi 2-chome, Fujisawa , Kanagawa 251-8555 , Japan., Wakabayashi T; Neuroscience Drug Discovery Unit, Research , Takeda Pharmaceutical Company Limited , 26-1, Muraoka-Higashi 2-chome, Fujisawa , Kanagawa 251-8555 , Japan., Hasui T; Neuroscience Drug Discovery Unit, Research , Takeda Pharmaceutical Company Limited , 26-1, Muraoka-Higashi 2-chome, Fujisawa , Kanagawa 251-8555 , Japan., Kawakita Y; Neuroscience Drug Discovery Unit, Research , Takeda Pharmaceutical Company Limited , 26-1, Muraoka-Higashi 2-chome, Fujisawa , Kanagawa 251-8555 , Japan., Imamura K; Neuroscience Drug Discovery Unit, Research , Takeda Pharmaceutical Company Limited , 26-1, Muraoka-Higashi 2-chome, Fujisawa , Kanagawa 251-8555 , Japan., Kato T; Neuroscience Drug Discovery Unit, Research , Takeda Pharmaceutical Company Limited , 26-1, Muraoka-Higashi 2-chome, Fujisawa , Kanagawa 251-8555 , Japan., Murakami M; Neuroscience Drug Discovery Unit, Research , Takeda Pharmaceutical Company Limited , 26-1, Muraoka-Higashi 2-chome, Fujisawa , Kanagawa 251-8555 , Japan., Ishii T; Neuroscience Drug Discovery Unit, Research , Takeda Pharmaceutical Company Limited , 26-1, Muraoka-Higashi 2-chome, Fujisawa , Kanagawa 251-8555 , Japan., Kikko Y; Neuroscience Drug Discovery Unit, Research , Takeda Pharmaceutical Company Limited , 26-1, Muraoka-Higashi 2-chome, Fujisawa , Kanagawa 251-8555 , Japan., Kasahara M; Neuroscience Drug Discovery Unit, Research , Takeda Pharmaceutical Company Limited , 26-1, Muraoka-Higashi 2-chome, Fujisawa , Kanagawa 251-8555 , Japan., Nakatani A; Neuroscience Drug Discovery Unit, Research , Takeda Pharmaceutical Company Limited , 26-1, Muraoka-Higashi 2-chome, Fujisawa , Kanagawa 251-8555 , Japan., Hiura Y; Neuroscience Drug Discovery Unit, Research , Takeda Pharmaceutical Company Limited , 26-1, Muraoka-Higashi 2-chome, Fujisawa , Kanagawa 251-8555 , Japan., Miyamoto M; Neuroscience Drug Discovery Unit, Research , Takeda Pharmaceutical Company Limited , 26-1, Muraoka-Higashi 2-chome, Fujisawa , Kanagawa 251-8555 , Japan., Saikatendu K; Takeda California, Inc. , 10410 Science Center Drive , San Diego , California 92121 , United States., Zou H; Takeda California, Inc. , 10410 Science Center Drive , San Diego , California 92121 , United States., Lane SW; Takeda California, Inc. , 10410 Science Center Drive , San Diego , California 92121 , United States., Lawson JD; Takeda California, Inc. , 10410 Science Center Drive , San Diego , California 92121 , United States., Imoto H; Neuroscience Drug Discovery Unit, Research , Takeda Pharmaceutical Company Limited , 26-1, Muraoka-Higashi 2-chome, Fujisawa , Kanagawa 251-8555 , Japan.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2019 May 23; Vol. 62 (10), pp. 4915-4935. Date of Electronic Publication: 2019 May 03.
DOI:	10.1021/acs.jmedchem.8b01630
Abstrakt:	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:	MEDLINE
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