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Combining traditional 2D and modern physical organic-derived descriptors to predict enhanced enantioselectivity for the key aza-Michael conjugate addition in the synthesis of Prevymis™ (letermovir)
Quantitative structure–activity relationships have an extensive history for optimizing drug candidates, yet they have only recently been applied in reaction development. In this report, the predictive power of multivariate parameterization has been explored toward the optimization of a catalyst prom...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Royal Society of Chemistry
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6124913/ https://www.ncbi.nlm.nih.gov/pubmed/30210766 http://dx.doi.org/10.1039/c8sc02089b |
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author | Metsänen, Toni T. Lexa, Katrina W. Santiago, Celine B. Chung, Cheol K. Xu, Yingju Liu, Zhijian Humphrey, Guy R. Ruck, Rebecca T. Sherer, Edward C. Sigman, Matthew S. |
author_facet | Metsänen, Toni T. Lexa, Katrina W. Santiago, Celine B. Chung, Cheol K. Xu, Yingju Liu, Zhijian Humphrey, Guy R. Ruck, Rebecca T. Sherer, Edward C. Sigman, Matthew S. |
author_sort | Metsänen, Toni T. |
collection | PubMed |
description | Quantitative structure–activity relationships have an extensive history for optimizing drug candidates, yet they have only recently been applied in reaction development. In this report, the predictive power of multivariate parameterization has been explored toward the optimization of a catalyst promoting an aza-Michael conjugate addition for the asymmetric synthesis of letermovir. A hybrid approach combining 2D QSAR and modern 3D physical organic parameters performed better than either approach in isolation. Using these predictive models, a series of new catalysts were identified, which catalyzed the reaction to provide the desired product in improved enantioselectivity relative to the parent catalyst. |
format | Online Article Text |
id | pubmed-6124913 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Royal Society of Chemistry |
record_format | MEDLINE/PubMed |
spelling | pubmed-61249132018-09-12 Combining traditional 2D and modern physical organic-derived descriptors to predict enhanced enantioselectivity for the key aza-Michael conjugate addition in the synthesis of Prevymis™ (letermovir) Metsänen, Toni T. Lexa, Katrina W. Santiago, Celine B. Chung, Cheol K. Xu, Yingju Liu, Zhijian Humphrey, Guy R. Ruck, Rebecca T. Sherer, Edward C. Sigman, Matthew S. Chem Sci Chemistry Quantitative structure–activity relationships have an extensive history for optimizing drug candidates, yet they have only recently been applied in reaction development. In this report, the predictive power of multivariate parameterization has been explored toward the optimization of a catalyst promoting an aza-Michael conjugate addition for the asymmetric synthesis of letermovir. A hybrid approach combining 2D QSAR and modern 3D physical organic parameters performed better than either approach in isolation. Using these predictive models, a series of new catalysts were identified, which catalyzed the reaction to provide the desired product in improved enantioselectivity relative to the parent catalyst. Royal Society of Chemistry 2018-07-18 /pmc/articles/PMC6124913/ /pubmed/30210766 http://dx.doi.org/10.1039/c8sc02089b Text en This journal is © The Royal Society of Chemistry 2018 http://creativecommons.org/licenses/by-nc/3.0/ This article is freely available. This article is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported Licence (CC BY-NC 3.0) |
spellingShingle | Chemistry Metsänen, Toni T. Lexa, Katrina W. Santiago, Celine B. Chung, Cheol K. Xu, Yingju Liu, Zhijian Humphrey, Guy R. Ruck, Rebecca T. Sherer, Edward C. Sigman, Matthew S. Combining traditional 2D and modern physical organic-derived descriptors to predict enhanced enantioselectivity for the key aza-Michael conjugate addition in the synthesis of Prevymis™ (letermovir) |
title | Combining traditional 2D and modern physical organic-derived descriptors to predict enhanced enantioselectivity for the key aza-Michael conjugate addition in the synthesis of Prevymis™ (letermovir)
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title_full | Combining traditional 2D and modern physical organic-derived descriptors to predict enhanced enantioselectivity for the key aza-Michael conjugate addition in the synthesis of Prevymis™ (letermovir)
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title_fullStr | Combining traditional 2D and modern physical organic-derived descriptors to predict enhanced enantioselectivity for the key aza-Michael conjugate addition in the synthesis of Prevymis™ (letermovir)
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title_full_unstemmed | Combining traditional 2D and modern physical organic-derived descriptors to predict enhanced enantioselectivity for the key aza-Michael conjugate addition in the synthesis of Prevymis™ (letermovir)
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title_short | Combining traditional 2D and modern physical organic-derived descriptors to predict enhanced enantioselectivity for the key aza-Michael conjugate addition in the synthesis of Prevymis™ (letermovir)
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title_sort | combining traditional 2d and modern physical organic-derived descriptors to predict enhanced enantioselectivity for the key aza-michael conjugate addition in the synthesis of prevymis™ (letermovir) |
topic | Chemistry |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6124913/ https://www.ncbi.nlm.nih.gov/pubmed/30210766 http://dx.doi.org/10.1039/c8sc02089b |
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