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Structure-Aided Identification and Optimization of Tetrahydro-isoquinolines as Novel PDE4 Inhibitors Leading to Discovery of an Effective Antipsoriasis Agent

文献类型：期刊论文

作者Zhang, Xianglei1,2; Dong, Guangyu2,3; Li, Heng1,2; Chen, Wuyan1; Li, Jian1; Feng, Chunlan1; Gu, Zhanni1; Zhu, Fenghua1; Zhang, Rui1,2; Li, Minjun4
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2019-06-13
卷号62期号:11页码:5579-5593
ISSN号0022-2623
DOI10.1021/acs.jmedchem.9b00518
通讯作者Tang, Wei(tangwei@simm.ac.cn) ; Liu, Hong(hliu@simm.ac.cn) ; Xu, Yechun(ycxu@simm.ac.cn)
英文摘要Psoriasis is a common, chronic inflammatory disease characterized by abnormal skin plaques, and the effectiveness of phosphodiesterase 4 (PDE4) inhibitor to lessen the symptoms of psoriasis has been proved. Aiming to find a novel PDE4 inhibitor acting as an effective, safe, and convenient therapeutic agent, we constructed a library consisting of berberine analogues, and compound 2 with a tetrahydroisoquinoline scaffold was identified as a novel and potent hit. The structure-aided and cell-based structure-activity relationship studies on a series of tetrahydro-isoquinolines lead to efficient discovery of a qualified lead compound (16) with the high potency and selectivity, well characterized binding mechanism, high cell permeability, good safety and pharmacokinetic profile, and impressive in vivo efficacy on antipsoriasis, in particular with a topical application. Thus, our study presents a prime example for efficient discovery of novel, potent lead compounds derived from natural products using a combination of medicinal chemistry, biochemical, biophysical, and pharmacological approaches.
WOS关键词PHOSPHODIESTERASE-4 INHIBITOR ; BERBERINE ; PSORIASIS ; MODEL ; INFLAMMATION ; MECHANISMS ; IMIQUIMOD ; PATHWAY ; MICE
资助项目National Key R&D Program of China[2016YFA0502301] ; National Science & Technology Major Project Key New Drug Creation and Manufacturing Program[2018ZX09711002-006-011] ; Strategic Priority Research Program of the Chinese Academy of Sciences Personalized Medicines-Molecular Signature-based Drug Discovery and Development[XDA12020231] ; National Natural Science Foundation of China[81620108027] ; National Natural Science Foundation of China[21632008] ; Science & Technology Commission of Shanghai Municipality, China[19431901100] ; Science & Technology Commission of Shanghai Municipality, China[18431907100]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000471834500022
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/289369]  
专题新药研究国家重点实验室
通讯作者Tang, Wei; Liu, Hong; Xu, Yechun
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, Lab Immunopharmacol,Drug Discovery & Design Ctr, State Key Lab Drug Res,CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China
2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
3.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
4.Chinese Acad Sci, Shanghai Adv Res Inst, Shanghai Synchrotron Radiat Facil, Shanghai 201210, Peoples R China
推荐引用方式
GB/T 7714		 Zhang, Xianglei,Dong, Guangyu,Li, Heng,et al. Structure-Aided Identification and Optimization of Tetrahydro-isoquinolines as Novel PDE4 Inhibitors Leading to Discovery of an Effective Antipsoriasis Agent[J]. JOURNAL OF MEDICINAL CHEMISTRY,2019,62(11):5579-5593.
APA Zhang, Xianglei.,Dong, Guangyu.,Li, Heng.,Chen, Wuyan.,Li, Jian.,...&Xu, Yechun.(2019).Structure-Aided Identification and Optimization of Tetrahydro-isoquinolines as Novel PDE4 Inhibitors Leading to Discovery of an Effective Antipsoriasis Agent.JOURNAL OF MEDICINAL CHEMISTRY,62(11),5579-5593.
MLA Zhang, Xianglei,et al."Structure-Aided Identification and Optimization of Tetrahydro-isoquinolines as Novel PDE4 Inhibitors Leading to Discovery of an Effective Antipsoriasis Agent".JOURNAL OF MEDICINAL CHEMISTRY 62.11(2019):5579-5593.

入库方式： OAI收割

来源：上海药物研究所

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