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

doi:10.1021/acs.jmedchem.9b00518

	Structure-Aided Identification and Optimization of Tetrahydro-isoquinolines as Novel PDE4 Inhibitors Leading to Discovery of an Effective Antipsoriasis Agent
	Zhang, Xianglei 1,2; Dong, Guangyu 2,3; Li, Heng 1,2; Chen, Wuyan 1; Li, Jian 1; Feng, Chunlan 1; Gu, Zhanni 1; Zhu, Fenghua 1; Zhang, Rui 1,2; Li, Minjun 4
刊名	JOURNAL OF MEDICINAL CHEMISTRY
	2019-06-13
卷号	62 期号:11 页码:5579-5593
ISSN号	0022-2623
DOI	10.1021/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.
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关键词	PHOSPHODIESTERASE-4 INHIBITOR ; BERBERINE ; PSORIASIS ; MODEL ; INFLAMMATION ; MECHANISMS ; IMIQUIMOD ; PATHWAY ; MICE
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000471834500022
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/289369]
专题	中国科学院上海药物研究所
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.