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.

中文翻译：

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发现强，选择性和脑渗透性的1 H-吡唑-5-基-1 H-吡咯并[2,3-b]吡啶作为间变性淋巴瘤激酶（ALK）抑制剂。

间变性淋巴瘤激酶（ALK）是受体酪氨酸激酶家族的成员，主要在大脑中表达，并参与神经元的发育和认知。但是，ALK在中枢神经系统（CNS）中的详细功能仍不清楚。为了阐明ALK在中枢神经系统中的作用，有必要发现一种有效的，选择性的和脑渗透性的ALK抑制剂。化合物1的共晶体结构指导的N-（2,4-二氟苄基）-3-（1H-吡唑-5-基）咪唑并[1,2-b]哒嗪-6-胺1的骨架跳跃和前导优化绑定到ALK导致（6-（1-（5-氟吡啶-2--2-基）乙氧基）-1-（5-甲基-1 H-吡唑-3-基）-1 H-吡咯[2， 3-b]吡啶-3-基）（（2 S）-2-甲基吗啉-4-基）甲酮13为高效，选择性和脑穿透性化合物。腹膜内给予化合物13可显着降低小鼠大脑海马和前额叶皮层的磷酸化ALK（p-ALK）水平。这些结果表明化合物13可以用作阐明ALK介导的脑功能机制和ALK抑制治疗潜力的有用化学探针。