Design, Synthesis, and SAR Studies of Heteroarylpyrimidines and Heteroaryltriazines as CB2R Ligands

doi:10.1002/cmdc.201800541

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	Design, Synthesis, and SAR Studies of Heteroarylpyrimidines and Heteroaryltriazines as CB2R Ligands
	Qian, Hai-Yan 1; Wang, Zhi-Long 2; Chen, Li-Li1 ; Pan, You-Lu 1; Xie, Xiao-Yu 1; Xie, Xin2 ; Chen, Jian-Zhong 1
刊名	CHEMMEDCHEM
	2018-11-20
卷号	13 期号:22 页码:2455-2463
关键词	cannabinoids CB1R CB2R heteroaryl pyrimidines heteroaryl triazines ligands
ISSN号	1860-7179
DOI	10.1002/cmdc.201800541
文献子类	Article
英文摘要	Herein we describe the design and synthesis of a new series of heteroarylpyrimidine/heteroaryltriazine derivatives on the basis of quinazoline-2,4(1H,3H)-diones as CB2R-selective ligands using a bioisosterism strategy. An acetamide group was explored to displace the enamine linker of the lead compound for the purpose of stereoisomerism elimination and hydrophilicity increase. As a result, some of the synthesized compounds showed high bioactivity and selectivity for CB2R in calcium mobilization assays, and four displayed CB2R agonist activity, with EC50 values below 30 nm. The compound exhibiting the highest agonist activity toward CB2R (EC50=7.53 +/- 3.15 nm) had a selectivity over CB1R of more than 1328-fold. Moreover, structure-activity relationship (SAR) studies indicated that the substituents on the nucleus play key roles in the functionality of a ligand, with one such example demonstrating CB2R antagonist activity. Additionally, molecular docking simulations were conducted with the aim of better understanding of these new derivatives in relation to the structural requirements for agonists/antagonists binding to CB2R.
资助项目	National Natural Science Foundation of China[81773638] ; National Natural Science Foundation of China[81425024] ; Ministry of Science and Technology[2014CB541906] ; Natural Science Foundation of Zhejiang Province[LZ18H300001]
WOS关键词	CANNABINOID RECEPTOR AGONISTS ; ENDOCANNABINOID SYSTEM ; MEDICINAL CHEMISTRY ; SELECTIVE LIGANDS ; CB1 ; DISCOVERY ; PROTEIN ; TARGET ; IDENTIFICATION ; PHARMACOLOGY
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	WILEY-V C H VERLAG GMBH
WOS记录号	WOS:000450866700010
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/279491]
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, Inst Mat Med, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Qian, Hai-Yan,Wang, Zhi-Long,Chen, Li-Li,et al. Design, Synthesis, and SAR Studies of Heteroarylpyrimidines and Heteroaryltriazines as CB2R Ligands[J]. CHEMMEDCHEM,2018,13(22):2455-2463.
APA	Qian, Hai-Yan.,Wang, Zhi-Long.,Chen, Li-Li.,Pan, You-Lu.,Xie, Xiao-Yu.,...&Chen, Jian-Zhong.(2018).Design, Synthesis, and SAR Studies of Heteroarylpyrimidines and Heteroaryltriazines as CB2R Ligands.CHEMMEDCHEM,13(22),2455-2463.
MLA	Qian, Hai-Yan,et al."Design, Synthesis, and SAR Studies of Heteroarylpyrimidines and Heteroaryltriazines as CB2R Ligands".CHEMMEDCHEM 13.22(2018):2455-2463.