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Design, Synthesis, and Evaluation of Dihydropyranopyrazole Derivatives as Novel PDE2 Inhibitors for the Treatment of Alzheimer’s Disease
Phosphodiesterase 2 (PDE2) has been regarded as a novel target for the treatment of Alzheimer’s disease (AD). In this study, we obtained (R)-LZ77 as a hit compound with moderate PDE2 inhibitory activity (IC(50) = 261.3 nM) using a high-throughput virtual screening method based on molecular dynamics....
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8160813/ https://www.ncbi.nlm.nih.gov/pubmed/34069639 http://dx.doi.org/10.3390/molecules26103034 |
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author | Zhou, Yan Li, Jinjian Yuan, Han Su, Rui Huang, Yue Huang, Yiyou Li, Zhe Wu, Yinuo Luo, Haibin Zhang, Chen Huang, Ling |
author_facet | Zhou, Yan Li, Jinjian Yuan, Han Su, Rui Huang, Yue Huang, Yiyou Li, Zhe Wu, Yinuo Luo, Haibin Zhang, Chen Huang, Ling |
author_sort | Zhou, Yan |
collection | PubMed |
description | Phosphodiesterase 2 (PDE2) has been regarded as a novel target for the treatment of Alzheimer’s disease (AD). In this study, we obtained (R)-LZ77 as a hit compound with moderate PDE2 inhibitory activity (IC(50) = 261.3 nM) using a high-throughput virtual screening method based on molecular dynamics. Then, we designed and synthesized 28 dihydropyranopyrazole derivatives as PDE2 inhibitors. Among them, compound (+)-11h was the most potent PDE2 inhibitor, with an IC(50) value of 41.5 nM. The molecular docking of PDE2-(+)-11h reveals that the 4-(trifluoromethyl)benzyl)oxyl side chain of the compound enters the H-pocket and forms strong hydrophobic interactions with L770/L809/F862, which improves inhibitory activity. The above results may provide insight for further structural optimization of highly potent PDE2 inhibitors and may lay the foundation for their use in the treatment of AD. |
format | Online Article Text |
id | pubmed-8160813 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-81608132021-05-29 Design, Synthesis, and Evaluation of Dihydropyranopyrazole Derivatives as Novel PDE2 Inhibitors for the Treatment of Alzheimer’s Disease Zhou, Yan Li, Jinjian Yuan, Han Su, Rui Huang, Yue Huang, Yiyou Li, Zhe Wu, Yinuo Luo, Haibin Zhang, Chen Huang, Ling Molecules Article Phosphodiesterase 2 (PDE2) has been regarded as a novel target for the treatment of Alzheimer’s disease (AD). In this study, we obtained (R)-LZ77 as a hit compound with moderate PDE2 inhibitory activity (IC(50) = 261.3 nM) using a high-throughput virtual screening method based on molecular dynamics. Then, we designed and synthesized 28 dihydropyranopyrazole derivatives as PDE2 inhibitors. Among them, compound (+)-11h was the most potent PDE2 inhibitor, with an IC(50) value of 41.5 nM. The molecular docking of PDE2-(+)-11h reveals that the 4-(trifluoromethyl)benzyl)oxyl side chain of the compound enters the H-pocket and forms strong hydrophobic interactions with L770/L809/F862, which improves inhibitory activity. The above results may provide insight for further structural optimization of highly potent PDE2 inhibitors and may lay the foundation for their use in the treatment of AD. MDPI 2021-05-19 /pmc/articles/PMC8160813/ /pubmed/34069639 http://dx.doi.org/10.3390/molecules26103034 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/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 (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Zhou, Yan Li, Jinjian Yuan, Han Su, Rui Huang, Yue Huang, Yiyou Li, Zhe Wu, Yinuo Luo, Haibin Zhang, Chen Huang, Ling Design, Synthesis, and Evaluation of Dihydropyranopyrazole Derivatives as Novel PDE2 Inhibitors for the Treatment of Alzheimer’s Disease |
title | Design, Synthesis, and Evaluation of Dihydropyranopyrazole Derivatives as Novel PDE2 Inhibitors for the Treatment of Alzheimer’s Disease |
title_full | Design, Synthesis, and Evaluation of Dihydropyranopyrazole Derivatives as Novel PDE2 Inhibitors for the Treatment of Alzheimer’s Disease |
title_fullStr | Design, Synthesis, and Evaluation of Dihydropyranopyrazole Derivatives as Novel PDE2 Inhibitors for the Treatment of Alzheimer’s Disease |
title_full_unstemmed | Design, Synthesis, and Evaluation of Dihydropyranopyrazole Derivatives as Novel PDE2 Inhibitors for the Treatment of Alzheimer’s Disease |
title_short | Design, Synthesis, and Evaluation of Dihydropyranopyrazole Derivatives as Novel PDE2 Inhibitors for the Treatment of Alzheimer’s Disease |
title_sort | design, synthesis, and evaluation of dihydropyranopyrazole derivatives as novel pde2 inhibitors for the treatment of alzheimer’s disease |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8160813/ https://www.ncbi.nlm.nih.gov/pubmed/34069639 http://dx.doi.org/10.3390/molecules26103034 |
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