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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...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
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.
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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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