Variations in the C-unit of bedaquiline provides analogues with improved biology and pharmacology
Copyright © 2019 Elsevier Ltd. All rights reserved..
Analogues of the anti-tuberculosis drug bedaquiline, bearing a 3,5-dimethoxy-4-pyridyl C-unit, retain high anti-bacterial potency yet exert less inhibition of the hERG potassium channel, in vitro, than the parent compound. Two of these analogues (TBAJ-587 and TBAJ-876) are now in preclinical development. The present study further explores structure-activity relationships across a range of related 3,5-disubstituted-4-pyridyl C-unit bedaquiline analogues of greatly varying lipophilicity (clogP from 8.16 to 1.89). This broader class shows similar properties to the 3,5-dimethoxy-4-pyridyl series, being substantially more potent in vitro and equally active in an in vivo (mouse) model than bedaquiline, while retaining a lower cardiovascular risk profile through greatly attenuated hERG inhibition.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:28 |
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| Enthalten in: |
Bioorganic & medicinal chemistry - 28(2020), 1 vom: 01. Jan., Seite 115213 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Sutherland, Hamish S [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 27.01.2021 Date Revised 27.01.2021 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.bmc.2019.115213 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM304124648 |
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| 100 | 1 | |a Sutherland, Hamish S |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Variations in the C-unit of bedaquiline provides analogues with improved biology and pharmacology |
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| 500 | |a Date Revised 27.01.2021 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2019 Elsevier Ltd. All rights reserved. | ||
| 520 | |a Analogues of the anti-tuberculosis drug bedaquiline, bearing a 3,5-dimethoxy-4-pyridyl C-unit, retain high anti-bacterial potency yet exert less inhibition of the hERG potassium channel, in vitro, than the parent compound. Two of these analogues (TBAJ-587 and TBAJ-876) are now in preclinical development. The present study further explores structure-activity relationships across a range of related 3,5-disubstituted-4-pyridyl C-unit bedaquiline analogues of greatly varying lipophilicity (clogP from 8.16 to 1.89). This broader class shows similar properties to the 3,5-dimethoxy-4-pyridyl series, being substantially more potent in vitro and equally active in an in vivo (mouse) model than bedaquiline, while retaining a lower cardiovascular risk profile through greatly attenuated hERG inhibition | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Research Support, U.S. Gov't, Non-P.H.S. | |
| 650 | 4 | |a CFU, colony-forming units | |
| 650 | 4 | |a HPLC, high-peformance liquid chromatography | |
| 650 | 4 | |a LDA, lithium diisopropylamide | |
| 650 | 4 | |a LORA, low oxygen recovery assay | |
| 650 | 4 | |a LiTMP, lithium tetramethylpiperidide | |
| 650 | 4 | |a M.tb, Mycobacterium tuberculosis | |
| 650 | 4 | |a MABA, microplate alamar blue assay | |
| 650 | 4 | |a MIC(90), minimum concentration for 90% inhibition | |
| 650 | 4 | |a TB, tuberculosis | |
| 650 | 4 | |a hERG, the alpha subunit of a K+ channel that contributes to the electrical activity of the heart | |
| 650 | 7 | |a Antitubercular Agents |2 NLM | |
| 650 | 7 | |a Diarylquinolines |2 NLM | |
| 650 | 7 | |a bedaquiline |2 NLM | |
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| 700 | 1 | |a Tong, Amy S T |e verfasserin |4 aut | |
| 700 | 1 | |a Choi, Peter J |e verfasserin |4 aut | |
| 700 | 1 | |a Blaser, Adrian |e verfasserin |4 aut | |
| 700 | 1 | |a Franzblau, Scott G |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 Lotlikar, Manisha |e verfasserin |4 aut | |
| 700 | 1 | |a Denny, William A |e verfasserin |4 aut | |
| 700 | 1 | |a Palmer, Brian D |e verfasserin |4 aut | |
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