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Synthetic Studies to Help Elucidate the Metabolism of the Preclinical Candidate TBAJ-876—A Less Toxic and More Potent Analogue of Bedaquiline
Bedaquiline is a novel drug approved in 2012 by the FDA for treatment of drug-resistant tuberculosis (TB). Although it shows high efficacy towards drug-resistant forms of TB, its use has been limited by the potential for significant side effects. In particular, bedaquiline is a very lipophilic compo...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7144385/ https://www.ncbi.nlm.nih.gov/pubmed/32245020 http://dx.doi.org/10.3390/molecules25061423 |
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author | Choi, Peter J. Conole, Daniel Sutherland, Hamish S. Blaser, Adrian Tong, Amy S.T. Cooper, Christopher B. Upton, Anna M. Palmer, Brian D. Denny, William A. |
author_facet | Choi, Peter J. Conole, Daniel Sutherland, Hamish S. Blaser, Adrian Tong, Amy S.T. Cooper, Christopher B. Upton, Anna M. Palmer, Brian D. Denny, William A. |
author_sort | Choi, Peter J. |
collection | PubMed |
description | Bedaquiline is a novel drug approved in 2012 by the FDA for treatment of drug-resistant tuberculosis (TB). Although it shows high efficacy towards drug-resistant forms of TB, its use has been limited by the potential for significant side effects. In particular, bedaquiline is a very lipophilic compound with an associated long terminal half-life and shows potent inhibition of the cardiac potassium hERG channel, resulting in QTc interval prolongation in humans that may result in cardiac arrhythmia. To address these issues, we carried out a drug discovery programme to develop an improved second generation analogue of bedaquiline. From this medicinal chemistry program, a candidate (TBAJ-876) has been selected to undergo further preclinical evaluation. During this evaluation, three major metabolites arising from TBAJ-876 were observed in several preclinical animal models. We report here our synthetic efforts to unequivocally structurally characterize these three metabolites through their independent directed synthesis. |
format | Online Article Text |
id | pubmed-7144385 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-71443852020-04-13 Synthetic Studies to Help Elucidate the Metabolism of the Preclinical Candidate TBAJ-876—A Less Toxic and More Potent Analogue of Bedaquiline Choi, Peter J. Conole, Daniel Sutherland, Hamish S. Blaser, Adrian Tong, Amy S.T. Cooper, Christopher B. Upton, Anna M. Palmer, Brian D. Denny, William A. Molecules Article Bedaquiline is a novel drug approved in 2012 by the FDA for treatment of drug-resistant tuberculosis (TB). Although it shows high efficacy towards drug-resistant forms of TB, its use has been limited by the potential for significant side effects. In particular, bedaquiline is a very lipophilic compound with an associated long terminal half-life and shows potent inhibition of the cardiac potassium hERG channel, resulting in QTc interval prolongation in humans that may result in cardiac arrhythmia. To address these issues, we carried out a drug discovery programme to develop an improved second generation analogue of bedaquiline. From this medicinal chemistry program, a candidate (TBAJ-876) has been selected to undergo further preclinical evaluation. During this evaluation, three major metabolites arising from TBAJ-876 were observed in several preclinical animal models. We report here our synthetic efforts to unequivocally structurally characterize these three metabolites through their independent directed synthesis. MDPI 2020-03-20 /pmc/articles/PMC7144385/ /pubmed/32245020 http://dx.doi.org/10.3390/molecules25061423 Text en © 2020 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 Choi, Peter J. Conole, Daniel Sutherland, Hamish S. Blaser, Adrian Tong, Amy S.T. Cooper, Christopher B. Upton, Anna M. Palmer, Brian D. Denny, William A. Synthetic Studies to Help Elucidate the Metabolism of the Preclinical Candidate TBAJ-876—A Less Toxic and More Potent Analogue of Bedaquiline |
title | Synthetic Studies to Help Elucidate the Metabolism of the Preclinical Candidate TBAJ-876—A Less Toxic and More Potent Analogue of Bedaquiline |
title_full | Synthetic Studies to Help Elucidate the Metabolism of the Preclinical Candidate TBAJ-876—A Less Toxic and More Potent Analogue of Bedaquiline |
title_fullStr | Synthetic Studies to Help Elucidate the Metabolism of the Preclinical Candidate TBAJ-876—A Less Toxic and More Potent Analogue of Bedaquiline |
title_full_unstemmed | Synthetic Studies to Help Elucidate the Metabolism of the Preclinical Candidate TBAJ-876—A Less Toxic and More Potent Analogue of Bedaquiline |
title_short | Synthetic Studies to Help Elucidate the Metabolism of the Preclinical Candidate TBAJ-876—A Less Toxic and More Potent Analogue of Bedaquiline |
title_sort | synthetic studies to help elucidate the metabolism of the preclinical candidate tbaj-876—a less toxic and more potent analogue of bedaquiline |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7144385/ https://www.ncbi.nlm.nih.gov/pubmed/32245020 http://dx.doi.org/10.3390/molecules25061423 |
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