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 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.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2020 |
|---|---|
| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:25 |
|---|---|
| Enthalten in: |
Molecules (Basel, Switzerland) - 25(2020), 6 vom: 20. März |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Choi, Peter J [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
78846I289Y |
|---|
| Anmerkungen: |
Date Completed 29.12.2020 Date Revised 29.12.2020 published: Electronic Citation Status MEDLINE |
|---|
| doi: |
10.3390/molecules25061423 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM308304470 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM308304470 | ||
| 003 | DE-627 | ||
| 005 | 20231225131441.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2020 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.3390/molecules25061423 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1027.xml |
| 035 | |a (DE-627)NLM308304470 | ||
| 035 | |a (NLM)32245020 | ||
| 035 | |a (PII)E1423 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Choi, Peter J |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Synthetic Studies to Help Elucidate the Metabolism of the Preclinical Candidate TBAJ-876-A Less Toxic and More Potent Analogue of Bedaquiline |
| 264 | 1 | |c 2020 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 29.12.2020 | ||
| 500 | |a Date Revised 29.12.2020 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Sirturo | |
| 650 | 4 | |a TBAJ-876 | |
| 650 | 4 | |a TMC207 | |
| 650 | 4 | |a bedaquiline | |
| 650 | 4 | |a bedaquiline analogues | |
| 650 | 4 | |a drug development | |
| 650 | 4 | |a mycobacterium tuberculosis | |
| 650 | 4 | |a tuberculosis | |
| 650 | 7 | |a Antitubercular Agents |2 NLM | |
| 650 | 7 | |a Diarylquinolines |2 NLM | |
| 650 | 7 | |a TBAJ-876 |2 NLM | |
| 650 | 7 | |a bedaquiline |2 NLM | |
| 650 | 7 | |a 78846I289Y |2 NLM | |
| 700 | 1 | |a Conole, Daniel |e verfasserin |4 aut | |
| 700 | 1 | |a Sutherland, Hamish S |e verfasserin |4 aut | |
| 700 | 1 | |a Blaser, Adrian |e verfasserin |4 aut | |
| 700 | 1 | |a Tong, Amy S T |e verfasserin |4 aut | |
| 700 | 1 | |a Cooper, Christopher B |e verfasserin |4 aut | |
| 700 | 1 | |a Upton, Anna M |e verfasserin |4 aut | |
| 700 | 1 | |a Palmer, Brian D |e verfasserin |4 aut | |
| 700 | 1 | |a Denny, William A |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Molecules (Basel, Switzerland) |d 2004 |g 25(2020), 6 vom: 20. März |w (DE-627)NLM172073448 |x 1420-3049 |7 nnns |
| 773 | 1 | 8 | |g volume:25 |g year:2020 |g number:6 |g day:20 |g month:03 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.3390/molecules25061423 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 25 |j 2020 |e 6 |b 20 |c 03 | ||