Design, synthesis, and biological evaluation of tetrahydroisoquinolines derivatives as novel, selective PDE4 inhibitors for antipsoriasis treatment

doi:10.1016/j.ejmech.2020.113004

	Design, synthesis, and biological evaluation of tetrahydroisoquinolines derivatives as novel, selective PDE4 inhibitors for antipsoriasis treatment
	Zhang, Rui 1,2,3; Li, Heng 3,4; Zhang, Xianglei 3,5; Li, Jian 1,2; Su, Haixia 3,5; Lu, Qiukai 3,4; Dong, Guangyu 1,2; Dou, Huixia 3,5; Fan, Chen 4; Gu, Zhanni 1,2
刊名	EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
	2021-02-05
卷号	211 页码:20
关键词	PDE4 inhibitors Tetrahydroisoquinoline Antipsoriasis
ISSN号	0223-5234
DOI	10.1016/j.ejmech.2020.113004
通讯作者	Tang, Wei(tangwei@simm.ac.cn) ; Xu, Yechun(ycxu@simm.ac.cn) ; Liu, Hong(hliu@simm.ac.cn)
英文摘要	Psoriasis is a kind of chronic inflammatory skin disorder, while the long-term use of conventional therapies for this disease are limited by severe adverse effects. Novel small molecules associated with new therapeutic mechanisms are greatly needed. It is known that phosphodiesterase 4 (PDE4) plays a central role in regulating inflammatory responses through hydrolyzing intracellular cyclic adenosine monophosphate (cAMP), making PDE4 to be an important target for the treatment of inflammatory diseases (e.g. psoriasis). In our previous work, we identified a series of novel PDE4 inhibitors with a tetrahydroisoquinoline scaffold through structure-based drug design, among which compound 1 showed moderate inhibition activity against PDE4. In this study, a series of novel tetrahydroisoquinoline derivatives were developed based on the crystal structure of PDE4D in complex with compound 1. Anti-inflammatory effects of these compounds were evaluated, and compound 36, with high safety, permeability and selectivity, exhibited significant inhibitory potency against the enzymatic activity of PDE4D and the TNF-alpha release from the LPS-stimulated RAW 264.7 and hPBMCs. Moreover, an in vivo study demonstrated that a topical administration of 36 achieved more significant efficacy than calcipotriol to improve the features of psoriasis-like skin inflammation. Overall, our study provides a basis for further development of tetrahydroisoquinoline-based PDE4 inhibitors against psoriasis. (C) 2020 Elsevier Masson SAS. All rights reserved.
资助项目	National Key R&D Program of China[2016YFA0502301] ; National Science & Technology Major Project Key New Drug Creation and ManufacturingProgram[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
出版者	ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
WOS记录号	WOS:000639375500006
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/295765]
专题	中国科学院上海药物研究所
通讯作者	Tang, Wei; Xu, Yechun; Liu, Hong
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Media, State Key Lab Drug Res, 555 Chong Zhi Rd, Shanghai 201203, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Media, CAS Key Lab Receptor Res, 555 Chong Zhi Rd, Shanghai 201203, Peoples R China 3.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China 4.Chinese Acad Sci, Shanghai Inst Mat Med, Lab Anti Inflammat & Immunopharmacol, 555 Chong Zhi Rd, Shanghai 201203, Peoples R China 5.Chinese Acad Sci, State Key Lab Drug Res, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, 501 Haike Rd, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Zhang, Rui,Li, Heng,Zhang, Xianglei,et al. Design, synthesis, and biological evaluation of tetrahydroisoquinolines derivatives as novel, selective PDE4 inhibitors for antipsoriasis treatment[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2021,211:20.
APA	Zhang, Rui.,Li, Heng.,Zhang, Xianglei.,Li, Jian.,Su, Haixia.,...&Liu, Hong.(2021).Design, synthesis, and biological evaluation of tetrahydroisoquinolines derivatives as novel, selective PDE4 inhibitors for antipsoriasis treatment.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,211,20.
MLA	Zhang, Rui,et al."Design, synthesis, and biological evaluation of tetrahydroisoquinolines derivatives as novel, selective PDE4 inhibitors for antipsoriasis treatment".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 211(2021):20.