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Design, Synthesis, and Biological Evaluation of N,N-Disubstituted-4-arylthiazole-2-methylamine Derivatives as Cholesteryl Ester Transfer Inhibitors

Cholesteryl ester transfer protein (CETP) has been identified as a potential target for cardiovascular disease (CVD) for its important role in the reverse cholesteryl transfer (RCT) process. In our previous work, compound 5 was discovered as a moderate CETP inhibitor. The replacement of the amide li...

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Autores principales: Wang, Xinran, Lin, Xuehua, Xu, Xuanqi, Li, Wei, Hao, Lijuan, Liu, Chunchi, Zhao, Dongmei, Cheng, Maosheng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6150381/
https://www.ncbi.nlm.nih.gov/pubmed/29112169
http://dx.doi.org/10.3390/molecules22111925
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author Wang, Xinran
Lin, Xuehua
Xu, Xuanqi
Li, Wei
Hao, Lijuan
Liu, Chunchi
Zhao, Dongmei
Cheng, Maosheng
author_facet Wang, Xinran
Lin, Xuehua
Xu, Xuanqi
Li, Wei
Hao, Lijuan
Liu, Chunchi
Zhao, Dongmei
Cheng, Maosheng
author_sort Wang, Xinran
collection PubMed
description Cholesteryl ester transfer protein (CETP) has been identified as a potential target for cardiovascular disease (CVD) for its important role in the reverse cholesteryl transfer (RCT) process. In our previous work, compound 5 was discovered as a moderate CETP inhibitor. The replacement of the amide linker by heterocyclic aromatics and then a series of N,N-substituted-4-arylthiazole-2-methylamine derivatives were designed by utilizing a conformational restriction strategy. Thirty-six compounds were synthesized and evaluated for their CETP inhibitory activities. Structure-activity relationship studies indicate that electron donor groups substituted ring A, and electron-withdrawing groups at the 4-position of ring B were critical for potency. Among these compounds, compound 30 exhibited excellent CETP inhibitory activity (IC(50) = 0.79 ± 0.02 μM) in vitro and showed an acceptable metabolic stability.
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spelling pubmed-61503812018-11-13 Design, Synthesis, and Biological Evaluation of N,N-Disubstituted-4-arylthiazole-2-methylamine Derivatives as Cholesteryl Ester Transfer Inhibitors Wang, Xinran Lin, Xuehua Xu, Xuanqi Li, Wei Hao, Lijuan Liu, Chunchi Zhao, Dongmei Cheng, Maosheng Molecules Article Cholesteryl ester transfer protein (CETP) has been identified as a potential target for cardiovascular disease (CVD) for its important role in the reverse cholesteryl transfer (RCT) process. In our previous work, compound 5 was discovered as a moderate CETP inhibitor. The replacement of the amide linker by heterocyclic aromatics and then a series of N,N-substituted-4-arylthiazole-2-methylamine derivatives were designed by utilizing a conformational restriction strategy. Thirty-six compounds were synthesized and evaluated for their CETP inhibitory activities. Structure-activity relationship studies indicate that electron donor groups substituted ring A, and electron-withdrawing groups at the 4-position of ring B were critical for potency. Among these compounds, compound 30 exhibited excellent CETP inhibitory activity (IC(50) = 0.79 ± 0.02 μM) in vitro and showed an acceptable metabolic stability. MDPI 2017-11-07 /pmc/articles/PMC6150381/ /pubmed/29112169 http://dx.doi.org/10.3390/molecules22111925 Text en © 2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Wang, Xinran
Lin, Xuehua
Xu, Xuanqi
Li, Wei
Hao, Lijuan
Liu, Chunchi
Zhao, Dongmei
Cheng, Maosheng
Design, Synthesis, and Biological Evaluation of N,N-Disubstituted-4-arylthiazole-2-methylamine Derivatives as Cholesteryl Ester Transfer Inhibitors
title Design, Synthesis, and Biological Evaluation of N,N-Disubstituted-4-arylthiazole-2-methylamine Derivatives as Cholesteryl Ester Transfer Inhibitors
title_full Design, Synthesis, and Biological Evaluation of N,N-Disubstituted-4-arylthiazole-2-methylamine Derivatives as Cholesteryl Ester Transfer Inhibitors
title_fullStr Design, Synthesis, and Biological Evaluation of N,N-Disubstituted-4-arylthiazole-2-methylamine Derivatives as Cholesteryl Ester Transfer Inhibitors
title_full_unstemmed Design, Synthesis, and Biological Evaluation of N,N-Disubstituted-4-arylthiazole-2-methylamine Derivatives as Cholesteryl Ester Transfer Inhibitors
title_short Design, Synthesis, and Biological Evaluation of N,N-Disubstituted-4-arylthiazole-2-methylamine Derivatives as Cholesteryl Ester Transfer Inhibitors
title_sort design, synthesis, and biological evaluation of n,n-disubstituted-4-arylthiazole-2-methylamine derivatives as cholesteryl ester transfer inhibitors
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6150381/
https://www.ncbi.nlm.nih.gov/pubmed/29112169
http://dx.doi.org/10.3390/molecules22111925
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