高度选择性、口服活性和强效间变性淋巴瘤激酶抑制剂（CH5424802）的设计与合成。
Design and synthesis of a highly selective, orally active and potent anaplastic lymphoma kinase inhibitor (CH5424802).
机构信息
Research Division, Chugai Pharmaceutical Co., Ltd, 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
出版信息
Bioorg Med Chem. 2012 Feb 1;20(3):1271-80. doi: 10.1016/j.bmc.2011.12.021. Epub 2011 Dec 22.
Anaplastic lymphoma kinase (ALK) receptor tyrosine kinase is considered an attractive therapeutic target for human cancers, especially non-small cell lung cancer (NSCLC). Our previous study revealed that 8,9-side-chains of 6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole scaffold crucially affected kinase selectivity, cellular activity, and metabolic stability. In this work, we optimized the side-chains and identified highly selective, orally active and potent ALK inhibitor CH5424802 (18a) as the clinical candidate.
间变性淋巴瘤激酶 (ALK) 受体酪氨酸激酶被认为是人类癌症，尤其是非小细胞肺癌 (NSCLC) 的一个有吸引力的治疗靶点。我们之前的研究表明，6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑骨架的 8,9-侧链对激酶选择性、细胞活性和代谢稳定性有至关重要的影响。在这项工作中，我们对侧链进行了优化，并鉴定出高选择性、口服活性和有效的 ALK 抑制剂 CH5424802 (18a) 作为临床候选药物。
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