Novel tetracyclic benzo[b]carbazolones as highly potent and orally bioavailable ALK inhibitors: Design, synthesis, and structure-activity relationship study

doi:10.1016/j.ejmech.2015.10.005

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	Novel tetracyclic benzo[b]carbazolones as highly potent and orally bioavailable ALK inhibitors: Design, synthesis, and structure-activity relationship study
	Jiang, Xiaolong 1,3; Zhou, Ji 2; Ai, Jing2 ; Song, Zilan 1; Peng, Xia 2; Xing, Li 1; Xi, Yong 2; Guo, Junfeng 1; Yao, Qizheng 3; Ding, Jian2
刊名	EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
	2015-11-13
卷号	105 页码:39-56
关键词	Benzo[b]carbazolones ALK inhibitors Anti-cancer Anti-resistance Non-small-cell lung cancer
ISSN号	0223-5234
DOI	10.1016/j.ejmech.2015.10.005
文献子类	Article
英文摘要	Four series of tetracyclic benzo[b]carbazolone compounds possessing more rotatable bonds and higher molecular flexibility were designed by either inserting a linker within the C8-side chain or by opening the middle ketone ring on the basis of compound 5 (Alectinib, CH5424802). Compound 15b was identified showing nearly identical high potency against both wild-type and the gatekeeper mutant ALK kinase (3.4 vs 3.9 nM). This compound has favorable PK profile with an oral bioavailability of 67.1% in rats. Moreover, compound 15b showed significant growth inhibition against ALK driven cancer cells and KARPAS-299 xenograft model. (C) 2015 Elsevier Masson SAS. All rights reserved.
资助项目	Chinese NSF[81430080] ; Chinese NSF[81125021] ; Chinese NSF[81373277] ; Chinese NSF[81473243] ; Chinese NSF[81321092] ; Major State Basic Research Development Program[2015CB910603] ; SIMM[CASIMM0120154002/2002]
WOS关键词	ANAPLASTIC LYMPHOMA KINASE ; CELL LUNG-CANCER ; CLINICALLY-ACQUIRED-RESISTANCE ; TYROSINE KINASE ; PHARMACOLOGICAL EVALUATION ; BIOLOGICAL EVALUATION ; CRIZOTINIB ; DISCOVERY ; CH5424802 ; EML4-ALK
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
WOS记录号	WOS:000364891400002
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/276323]
专题	药理学第一研究室中科院受体结构与功能重点实验室新药研究国家重点实验室药物化学研究室
通讯作者	Zhang, Ao
作者单位	1.Chinese Acad Sci, CAS Key Lab Receptor Res, Synthet Organ & Med Chem Lab, SIMM, Shanghai 201203, Peoples R China; 2.Chinese Acad Sci, Div Antitumor Pharmacol, State Key Lab Drug Res, SIMM, Shanghai 201203, Peoples R China; 3.China Pharmaceut Univ, Dept Med Chem, Nanjing 210009, Peoples R China
推荐引用方式 GB/T 7714	Jiang, Xiaolong,Zhou, Ji,Ai, Jing,et al. Novel tetracyclic benzo[b]carbazolones as highly potent and orally bioavailable ALK inhibitors: Design, synthesis, and structure-activity relationship study[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2015,105:39-56.
APA	Jiang, Xiaolong.,Zhou, Ji.,Ai, Jing.,Song, Zilan.,Peng, Xia.,...&Zhang, Ao.(2015).Novel tetracyclic benzo[b]carbazolones as highly potent and orally bioavailable ALK inhibitors: Design, synthesis, and structure-activity relationship study.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,105,39-56.
MLA	Jiang, Xiaolong,et al."Novel tetracyclic benzo[b]carbazolones as highly potent and orally bioavailable ALK inhibitors: Design, synthesis, and structure-activity relationship study".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 105(2015):39-56.