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Design, synthesis and pharmacological evaluation of tricyclic derivatives as selective RXFP4 agonists

文献类型：期刊论文

作者Lin, Lin1; Lin, Guangyao3,4; Zhou, Qingtong5; Bathgate, Ross A. D.6; Gong, Grace Qun2,7; Yang, Dehua2,4,7; Liu, Qing2,7; Wang, Ming-Wei1,2,3,4,5,7
刊名BIOORGANIC CHEMISTRY
出版日期2021-05-01
卷号110页码:17
关键词Synthesis Structure-activity relationship Relaxin family peptide receptor 4 Selective agonist Molecular docking
ISSN号0045-2068
DOI10.1016/j.bioorg.2021.104782
通讯作者Yang, Dehua(dhyang@simm.ac.cn) ; Liu, Qing(qliu@simm.ac.cn) ; Wang, Ming-Wei(mwwang@simm.ac.cn)
英文摘要Relaxin family peptide receptors (RXFPs) are the potential therapeutic targets for neurological, cardiovascular, and metabolic indications. Among them, RXFP3 and RXFP4 (formerly known as GPR100 or GPCR142) are homologous class A G protein-coupled receptors with short N-terminal domain. Ligands of RXFP3 or RXFP4 are only limited to endogenous peptides and their analogues, and no natural product or synthetic agonists have been reported to date except for a scaffold of indole-containing derivatives as dual agonists of RXFP3 and RXFP4. In this study, a new scaffold of tricyclic derivatives represented by compound 7a was disclosed as a selective RXFP4 agonist after a high-throughput screening campaign against a diverse library of 52,000 synthetic and natural compounds. Two rounds of structural modification around this scaffold were performed focusing on three parts: 2-chlorophenyl group, 4-hydroxylphenyl group and its skeleton including cyclohexane-1,3-dione and 1,2,4-triazole group. Compound 14b with a new skeleton of 7,9-dihydro-4H-thiopyrano[3,4-d][1,2,4]triazolo[1,5-a] pyrimidin-8(5H)-one was thus obtained. The enantiomers of 7a and 14b were also resolved with their 9-(S)conformer favoring RXFP4 agonism. Compared with 7a, compound 9-(S)-14b exhibited 2.3-fold higher efficacy and better selectivity for RXFP4 (selective ratio of RXFP4 vs. RXFP3 for 9-(S)-14b and 7a were 26.9 and 13.9, respectively).
WOS关键词RELAXIN FAMILY PEPTIDES ; RECEPTOR ; LIGAND
资助项目National Natural Science Foundation of China[81872915] ; National Natural Science Foundation of China[82073904] ; National Natural Science Foundation of China[21302202] ; National Natural Science Foundation of China[81973373] ; National Natural Science Foundation of China[81773792] ; National Science & Technology Major Project Key New Drug Creation and Manufacturing Program of China[2018ZX09735-001] ; National Science & Technology Major Project Key New Drug Creation and Manufacturing Program of China[2018ZX09711002-002-005] ; National Science & Technology Major Project Key New Drug Creation and Manufacturing Program of China[2018ZX09711002-002-011] ; National Key R&D Program of China[2018YFA0507000] ; Novo Nordisk-CAS Research Fund[NNCAS-2017-1-CC]
WOS研究方向Biochemistry & Molecular Biology ; Chemistry
语种英语
WOS记录号WOS:000670626400008
出版者ACADEMIC PRESS INC ELSEVIER SCIENCE
源URL[http://119.78.100.183/handle/2S10ELR8/296907]  
专题中国科学院上海药物研究所
通讯作者Yang, Dehua; Liu, Qing; Wang, Ming-Wei
作者单位1.Fudan Univ, Sch Pharm, Shanghai 201203, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, Key Lab Receptor Res, Shanghai 201203, Peoples R China
3.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
4.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
5.Fudan Univ, Sch Basic Med Sci, Shanghai 200032, Peoples R China
6.Univ Melbourne, Florey Inst Neurosci & Mental Hlth, Dept Biochem & Mol Biol, Parkville, Vic 3052, Australia
7.Chinese Acad Sci, Natl Ctr Drug Screening, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Lin, Lin,Lin, Guangyao,Zhou, Qingtong,et al. Design, synthesis and pharmacological evaluation of tricyclic derivatives as selective RXFP4 agonists[J]. BIOORGANIC CHEMISTRY,2021,110:17.
APA Lin, Lin.,Lin, Guangyao.,Zhou, Qingtong.,Bathgate, Ross A. D..,Gong, Grace Qun.,...&Wang, Ming-Wei.(2021).Design, synthesis and pharmacological evaluation of tricyclic derivatives as selective RXFP4 agonists.BIOORGANIC CHEMISTRY,110,17.
MLA Lin, Lin,et al."Design, synthesis and pharmacological evaluation of tricyclic derivatives as selective RXFP4 agonists".BIOORGANIC CHEMISTRY 110(2021):17.

入库方式： OAI收割

来源：上海药物研究所

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