Discovery of Potent Antiallergic Agents Based on an o-Aminopyridinyl Alkynyl Scaffold
文献类型：期刊论文
| 作者 | Xie, Zhicheng1,2; Xiang, Caigui2,3; Li, Xin1,2; Fan, Chen3; Chen, Taiwen1,2; Liu, Moting3; Ma, Yanjie1; Bai, Fang3; Tang, Wei2,3 ; Hu, Youhong1,2,4
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| 刊名 | JOURNAL OF MEDICINAL CHEMISTRY
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| 出版日期 | 2021-09-23 |
| 卷号 | 64期号:18页码:13588-13603 |
| ISSN号 | 0022-2623 |
| DOI | 10.1021/acs.jmedchem.1c00976 |
| 文献子类 | Article |
| 英文摘要 | Effective therapeutic agents are highly desired for immune-mediated allergic diseases. Herein, we report the design, synthesis, and structure-activity relationship of an o-amino-pyridinyl alkyne series as novel orally bioavailable antiallergic agents, which was identified through phenotypic screening. Compound optimization yielded a highly potent compound 36, which effectively suppressed mast cell degranulation in a dose-dependent manner (IC50, 2.54 nM for RBL-2H3 cells; 48.28 nM for peritoneal mast cells (PMCs)) with a good therapeutic index. It also regulated the activation of FceRI-mediated downstream signaling proteins in IgE/Ag-stimulated RBL-2H3 cells. In addition, 36 exhibited excellent in vivo pharmacokinetic properties and antiallergic efficacy in both passive systemic anaphylaxis (PSA) and house dust mite (HDM)-induced murine models of pulmonary allergic inflammation. Furthermore, preliminary analysis of the kinases profile identified Src-family kinases as potential targets for 36. Compound 36 may serve as a new valuable lead compound for future antiallergic drug discovery. |
| WOS关键词 | TYROSINE KINASE INHIBITORS ; MAST-CELLS ; ALLERGY ; ANAPHYLAXIS ; RESPONSES ; BLOCKADE ; DISEASE ; MODEL |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000701513400027 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/309371]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Tang, Wei; Hu, Youhong |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China; 3.Chinese Acad Sci, Shanghai Inst Mat Med, Lab Immunopharmacol, Shanghai 201203, Peoples R China; 4.Chinese Acad Sci, Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Hangzhou 310024, Peoples R China |
| 推荐引用方式 GB/T 7714 | Xie, Zhicheng,Xiang, Caigui,Li, Xin,et al. Discovery of Potent Antiallergic Agents Based on an o-Aminopyridinyl Alkynyl Scaffold[J]. JOURNAL OF MEDICINAL CHEMISTRY,2021,64(18):13588-13603. |
| APA | Xie, Zhicheng.,Xiang, Caigui.,Li, Xin.,Fan, Chen.,Chen, Taiwen.,...&Hu, Youhong.(2021).Discovery of Potent Antiallergic Agents Based on an o-Aminopyridinyl Alkynyl Scaffold.JOURNAL OF MEDICINAL CHEMISTRY,64(18),13588-13603. |
| MLA | Xie, Zhicheng,et al."Discovery of Potent Antiallergic Agents Based on an o-Aminopyridinyl Alkynyl Scaffold".JOURNAL OF MEDICINAL CHEMISTRY 64.18(2021):13588-13603. |
入库方式： OAI收割
来源：上海药物研究所
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