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Discovery and synthesis of 6,7,8,9-tetrahydro-5H-pyrido[4,3-c]azepin-5-one-based novel chemotype CCR2 antagonists via scaffold hopping strategy

文献类型：期刊论文

作者Qin, Li-Huai1,2,3; Wang, Zhi-Long2; Xie, Xin2; Long, Ya-Qiu2,3
刊名BIOORGANIC & MEDICINAL CHEMISTRY
出版日期2018-07-23
卷号26期号:12页码:3559-3572
关键词6,7,8,9-Tetrahydro-5H-pyrido[43-c]azepin-5-one 3,4-Dihydro-2,6-naphthyridin-1(2H)-one CCR2 antagonist Scaffold hopping Structure-activity relationship Selectivity of CCR2 over CCR5
ISSN号0968-0896
DOI10.1016/j.bmc.2018.05.027
文献子类Article
英文摘要The chemokine CC receptor subtype 2 (CCR2) has attracted intensive interest for drug development in diverse therapeutic areas, including chronic inflammatory diseases, diabetes, neuropathic pain, atherogenesis and cancer. By employing a cut-and-sew scaffold hopping strategy, we identified an active scaffold of 3,4-dihydro2,6-naphthyridin-1(2H)-one as the central pharmacophore to derive novel CCR2 antagonists. Systematic structure-activity relationship study with respect to the ring size and the substitution on the naphthyridinone ring gave birth to 1-arylamino-6-alkylheterocycle-6,7,8,9-tetrahydro-5H-pyrido[4,3-c]azepin-5-ones as a brand new chemotype of CCR2 antagonists with nanomolar inhibitory activity. The best antagonism activity in this series was exemplified by compound 13a, which combined the optimal substitutions of 3,4-dichlorophenylamino at C-1 and 3-(4-(N-methylmethylsulfonamido)piperidin-1-yl)propyl at N-6 position, leading to an IC50 value of 61 nM and 10-fold selectivity for CCR2 over CCR5. Efficient and general synthesis was established to construct the innovative core structure and derive the compound collections. This is the first report on our designed 6,7,8,9-tetrahydro-5H-pyrido[4,3-c]azepin-5-one as novel CCR2 antagonist scaffold and its synthesis.
WOS关键词CHEMOKINE RECEPTOR ANTAGONISTS ; BIOLOGICAL EVALUATION
资助项目National Natural Science Foundation of China[81325020] ; National Natural Science Foundation of China[81361120410] ; National Natural Science Foundation of China[81761128022] ; National Natural Science Foundation of China[21772214]
WOS研究方向Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Chemistry
语种英语
WOS记录号WOS:000436779400044
出版者PERGAMON-ELSEVIER SCIENCE LTD
源URL[http://119.78.100.183/handle/2S10ELR8/279654]  
专题国家新药筛选中心
通讯作者Xie, Xin; Long, Ya-Qiu
作者单位1.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China;
3.Soochow Univ, Coll Pharmaceut Sci, 199 Renai Rd, Suzhou 215123, Peoples R China;
推荐引用方式
GB/T 7714		 Qin, Li-Huai,Wang, Zhi-Long,Xie, Xin,et al. Discovery and synthesis of 6,7,8,9-tetrahydro-5H-pyrido[4,3-c]azepin-5-one-based novel chemotype CCR2 antagonists via scaffold hopping strategy[J]. BIOORGANIC & MEDICINAL CHEMISTRY,2018,26(12):3559-3572.
APA Qin, Li-Huai,Wang, Zhi-Long,Xie, Xin,&Long, Ya-Qiu.(2018).Discovery and synthesis of 6,7,8,9-tetrahydro-5H-pyrido[4,3-c]azepin-5-one-based novel chemotype CCR2 antagonists via scaffold hopping strategy.BIOORGANIC & MEDICINAL CHEMISTRY,26(12),3559-3572.
MLA Qin, Li-Huai,et al."Discovery and synthesis of 6,7,8,9-tetrahydro-5H-pyrido[4,3-c]azepin-5-one-based novel chemotype CCR2 antagonists via scaffold hopping strategy".BIOORGANIC & MEDICINAL CHEMISTRY 26.12(2018):3559-3572.

入库方式： OAI收割

来源：上海药物研究所

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