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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| Format: | Article |
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MDPI AG
2020-03-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/25/6/1423 |
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| author | Peter J. Choi Daniel Conole Hamish S. Sutherland Adrian Blaser Amy S.T. Tong Christopher B. Cooper Anna M. Upton Brian D. Palmer William A. Denny |
| author_facet | Peter J. Choi Daniel Conole Hamish S. Sutherland Adrian Blaser Amy S.T. Tong Christopher B. Cooper Anna M. Upton Brian D. Palmer William A. Denny |
| author_sort | Peter J. Choi |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-20T01:20:33Z |
| format | Article |
| id | doaj.art-2c871cfcedf94323adc59bd51b4d499c |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-12-20T01:20:33Z |
| publishDate | 2020-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-2c871cfcedf94323adc59bd51b4d499c2022-12-21T19:58:27ZengMDPI AGMolecules1420-30492020-03-01256142310.3390/molecules25061423molecules25061423Synthetic Studies to Help Elucidate the Metabolism of the Preclinical Candidate TBAJ-876—A Less Toxic and More Potent Analogue of BedaquilinePeter J. Choi0Daniel Conole1Hamish S. Sutherland2Adrian Blaser3Amy S.T. Tong4Christopher B. Cooper5Anna M. Upton6Brian D. Palmer7William A. Denny8Auckland Cancer Society Research Centre, School of Medical Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New ZealandAuckland Cancer Society Research Centre, School of Medical Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New ZealandAuckland Cancer Society Research Centre, School of Medical Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New ZealandAuckland Cancer Society Research Centre, School of Medical Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New ZealandAuckland Cancer Society Research Centre, School of Medical Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New ZealandGlobal Alliance for TB Drug Development, 40 Wall St, New York, NY 10005, USAGlobal Alliance for TB Drug Development, 40 Wall St, New York, NY 10005, USAAuckland Cancer Society Research Centre, School of Medical Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New ZealandAuckland Cancer Society Research Centre, School of Medical Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New ZealandBedaquiline 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.https://www.mdpi.com/1420-3049/25/6/1423bedaquilinetmc207sirturobedaquiline analoguestbaj-876mycobacterium tuberculosistuberculosisdrug development |
| spellingShingle | Peter J. Choi Daniel Conole Hamish S. Sutherland Adrian Blaser Amy S.T. Tong Christopher B. Cooper Anna M. Upton Brian D. Palmer William A. Denny Synthetic Studies to Help Elucidate the Metabolism of the Preclinical Candidate TBAJ-876—A Less Toxic and More Potent Analogue of Bedaquiline Molecules bedaquiline tmc207 sirturo bedaquiline analogues tbaj-876 mycobacterium tuberculosis tuberculosis drug development |
| 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 | bedaquiline tmc207 sirturo bedaquiline analogues tbaj-876 mycobacterium tuberculosis tuberculosis drug development |
| url | https://www.mdpi.com/1420-3049/25/6/1423 |
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