Discovery and structural optimization of 1-phenyl-3-(1-phenylethyl)urea derivatives as novel inhibitors of CRAC channel
文献类型：期刊论文
| 作者 | Zhang, Hai-zhen1; Xu, Xiao-lan2; Chen, Hua-yan1; Ali, Sher2; Wang, Dan2; Yu, Jun-wei2; Xu, Tao2; Nan, Fa-jun1
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| 刊名 | ACTA PHARMACOLOGICA SINICA
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| 出版日期 | 2015-09 |
| 卷号 | 36期号:9页码:1137-1144 |
| 关键词 | CRAC channel ORAI1 1-phenyl-3-(1-phenylethyl)urea YM58483 high-throughput screening IL-2 production structure modification SAR |
| ISSN号 | 1671-4083 |
| DOI | 10.1038/aps.2015.52 |
| 文献子类 | Article |
| 英文摘要 | Aim: Ca2+-release-activated Ca2+ (CRAC) channel, a subfamily of store-operated channels, is formed by calcium release-activated calcium modulator 1 (ORAI1), and gated by stromal interaction molecule 1 (STIM1). CRAC channel may be a novel target for the treatment of immune disorders and allergy. The aim of this study was to identify novel small molecule CRAC channel inhibitors. Methods: HEK293 cells stably co-expressing both ORAI1 and STIM1 were used for high-throughput screening. A hit, 1-phenyl-3-(1-phenylethyl)urea, was identified that inhibited CRAC channels by targeting ORAI1. Five series of its derivatives were designed and synthesized, and their primary structure-activity relationships (SARs) were analyzed. All derivatives were assessed for their effects on Ca2+ influx through CRAC channels on HEK293 cells, cytotoxicity in Jurkat cells, and IL-2 production in Jurkat cells expressing ORAI1-SS-eGFP. Results: A total of 19 hits were discovered in libraries containing 32 000 compounds using the high-throughput screening. 1-Phenyl-3-(1-phenylethyl) urea inhibited Ca2+ influx with IC50 of 3.25 +/- 0.17 mu mol/L. SAR study on its derivatives showed that the alkyl substituent on the a-position of the left-side benzylic amine (R1) was essential for Ca2+ influx inhibition and that the S-configuration was better than the R-configuration. The derivatives in which the right-side R3 was substituted by an electron-donating group showed more potent inhibitory activity than those that were substituted by electron-withdrawing groups. Furthermore, the free N-H of urea was not necessary to maintain the high potency of Ca2+ influx inhibition. The N, N'-disubstituted or N'-substituted derivatives showed relatively low cytotoxicity but maintained the ability to inhibit IL-2 production. Among them, compound 5b showed an improved inhibition of IL-2 production and low cytotoxicity. Conclusion: 1-Phenyl-3-(1-phenylethyl) urea is a novel CRAC channel inhibitor that specifically targets ORAI1. This study provides a new chemical scaffold for design and development of CRAC channel inhibitors with improved Ca2+ influx inhibition, immune inhibition and low cytotoxicity. |
| WOS关键词 | ACTIVATED CA2+ CHANNELS ; T-LYMPHOCYTES ; MAST-CELLS ; CALCIUM-CHANNELS ; IL-2 PRODUCTION ; RELEASE ; STIM1 ; DEPLETION ; IMMUNODEFICIENCY ; POTENTIATION |
| 资助项目 | National Science and Technology Major Projects for Major New Drugs Innovation and Development[2012ZX09304011] ; National Science and Technology Major Projects for Major New Drugs Innovation and Development[2013ZX09507002] ; Chinese Academy of Science for Technological Innovation and Cross-Team Collaboration[00000000] ; State Key Laboratory of Drug Research[00000000] ; National Key Laboratory of Biomacromolecules[00000000] ; National Natural Science Foundation of China[81102456] ; National Natural Science Foundation of China[81373422] |
| WOS研究方向 | Chemistry ; Pharmacology & Pharmacy |
| 语种 | 英语 |
| CSCD记录号 | CSCD:5510640 |
| WOS记录号 | WOS:000360840200011 |
| 出版者 | ACTA PHARMACOLOGICA SINICA |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/276418]  |
| 专题 | 国家新药筛选中心 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 |
| 通讯作者 | Xu, Tao |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 2.Chinese Acad Sci, Inst Biophys, Natl Key Lab Biomacromol, Beijing 100101, Peoples R China |
| 推荐引用方式 GB/T 7714 | Zhang, Hai-zhen,Xu, Xiao-lan,Chen, Hua-yan,et al. Discovery and structural optimization of 1-phenyl-3-(1-phenylethyl)urea derivatives as novel inhibitors of CRAC channel[J]. ACTA PHARMACOLOGICA SINICA,2015,36(9):1137-1144. |
| APA | Zhang, Hai-zhen.,Xu, Xiao-lan.,Chen, Hua-yan.,Ali, Sher.,Wang, Dan.,...&Nan, Fa-jun.(2015).Discovery and structural optimization of 1-phenyl-3-(1-phenylethyl)urea derivatives as novel inhibitors of CRAC channel.ACTA PHARMACOLOGICA SINICA,36(9),1137-1144. |
| MLA | Zhang, Hai-zhen,et al."Discovery and structural optimization of 1-phenyl-3-(1-phenylethyl)urea derivatives as novel inhibitors of CRAC channel".ACTA PHARMACOLOGICA SINICA 36.9(2015):1137-1144. |
入库方式： OAI收割
来源：上海药物研究所
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