Developing pyridazine-3-carboxamides to be CB2 agonists: The design, synthesis, structure-activity relationships and docking studies

doi:10.1016/j.ejmech.2017.05.060

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	Developing pyridazine-3-carboxamides to be CB2 agonists: The design, synthesis, structure-activity relationships and docking studies
	Qian, Hai-Yan 1; Wang, Zhi-Long 2; Xie, Xiao-Yu 1; Pan, You-Lu 1; Li, Gang-Jian 1; Xie, Xin2 ; Chen, Jian-Zhong 1
刊名	EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
	2017-09-08
卷号	137 页码:598-611
关键词	Pyridazine-3-carboxamides CB2 agonist Structure-activity relationships Molecular docking logP
ISSN号	0223-5234
DOI	10.1016/j.ejmech.2017.05.060
文献子类	Article
英文摘要	Herein, we described the design and synthesis of a series of pyridazine-3-carboxamides to be CB2-selective agonists via a combination of scaffold hopping and bioisosterism strategies. The compounds were subjected to assessment of their potential activities through calcium mobilization assays. Among the tested derivatives, more than half of these compounds exhibited moderate to potent CB2 agonist activity. Six compounds showed EC50 values below 35 nM, and several derivatives also exhibited significantly enhanced potency and high selectivity at the CB2 receptor over the CB1 receptor. Specifically, compound 26 showed the highest CB2 agonist activity (EC50 = 3.665 +/- 0.553 nM) and remarkable selectivity (Selectivity Index > 2729) against CB1. In addition, logPs of some representative compounds were measured to display significantly decreased values in comparison with GW842166X. Furthermore, docking simulations were conducted to explain the interaction mode of this series. (C) 2017 Elsevier Masson SAS. All rights reserved.
资助项目	National Natural Science Foundation of China[30973637] ; National Natural Science Foundation of China[81425024] ; National Natural Science Foundation of China[81473135] ; Ministry of Science and Technology[2014CB541906] ; Zhejiang Technology Office[2010R10048]
WOS关键词	CANNABINOID TYPE-2 RECEPTOR ; PHARMACOLOGICAL EVALUATION ; NEUROPATHIC PAIN ; LIGANDS ; SYSTEM ; TARGET ; IDENTIFICATION ; ANTAGONISTS ; INHIBITION ; DISCOVERY
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:000407412200038
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/272487]
专题	国家新药筛选中心
通讯作者	Xie, Xin; Chen, Jian-Zhong
作者单位	1.Zhejiang Univ, Coll Pharmaceut Sci, Hangzhou 310058, Zhejiang, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Qian, Hai-Yan,Wang, Zhi-Long,Xie, Xiao-Yu,et al. Developing pyridazine-3-carboxamides to be CB2 agonists: The design, synthesis, structure-activity relationships and docking studies[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2017,137:598-611.
APA	Qian, Hai-Yan.,Wang, Zhi-Long.,Xie, Xiao-Yu.,Pan, You-Lu.,Li, Gang-Jian.,...&Chen, Jian-Zhong.(2017).Developing pyridazine-3-carboxamides to be CB2 agonists: The design, synthesis, structure-activity relationships and docking studies.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,137,598-611.
MLA	Qian, Hai-Yan,et al."Developing pyridazine-3-carboxamides to be CB2 agonists: The design, synthesis, structure-activity relationships and docking studies".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 137(2017):598-611.