dc.contributor.author |
Sutherland, Hamish S |
|
dc.contributor.author |
Tong, Amy ST |
|
dc.contributor.author |
Choi, Peter J |
|
dc.contributor.author |
Blaser, Adrian |
|
dc.contributor.author |
Conole, Daniel |
|
dc.contributor.author |
Franzblau, Scott G |
|
dc.contributor.author |
Lotlikar, Manisha U |
|
dc.contributor.author |
Cooper, Christopher B |
|
dc.contributor.author |
Upton, Anna M |
|
dc.contributor.author |
Denny, William A |
|
dc.contributor.author |
Palmer, Brian D |
|
dc.coverage.spatial |
England |
|
dc.date.accessioned |
2022-02-09T20:58:26Z |
|
dc.date.available |
2022-02-09T20:58:26Z |
|
dc.date.issued |
2019-4 |
|
dc.identifier.citation |
Bioorganic & medicinal chemistry 27(7):1292-1307 Apr 2019 |
|
dc.identifier.issn |
0968-0896 |
|
dc.identifier.uri |
https://hdl.handle.net/2292/58126 |
|
dc.description.abstract |
Bedaquiline is a new drug of the diarylquinoline class that has proven to be clinically effective against drug-resistant tuberculosis, but has a cardiac liability (prolongation of the QT interval) due to its potent inhibition of the cardiac potassium channel protein hERG. Bedaquiline is highly lipophilic and has an extremely long terminal half-life, so has the potential for more-than-desired accumulation in tissues during the relatively long treatment durations required to cure TB. The present work is part of a program that seeks to identify a diarylquinoline that is as potent as bedaquiline against Mycobacterium tuberculosis, with lower lipophilicity, higher clearance, and lower risk for QT prolongation. Previous work led to the identification of compounds with greatly-reduced lipophilicity compounds that retain good anti-tubercular activity in vitro and in mouse models of TB, but has not addressed the hERG blockade. We now present compounds where the C-unit naphthalene is replaced by a 3,5-dialkoxy-4-pyridyl, demonstrate more potent in vitro and in vivo anti-tubercular activity, with greatly attenuated hERG blockade. Two examples of this series are in preclinical development. |
|
dc.format.medium |
Print-Electronic |
|
dc.language |
eng |
|
dc.publisher |
Elsevier BV |
|
dc.relation.ispartofseries |
Bioorganic & medicinal chemistry |
|
dc.rights |
Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. |
|
dc.rights.uri |
https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm |
|
dc.rights.uri |
https://creativecommons.org/licenses/by/4.0/ |
|
dc.subject |
Humans |
|
dc.subject |
Mycobacterium tuberculosis |
|
dc.subject |
Pyridines |
|
dc.subject |
Potassium Channel Blockers |
|
dc.subject |
Antitubercular Agents |
|
dc.subject |
Microbial Sensitivity Tests |
|
dc.subject |
Molecular Structure |
|
dc.subject |
Structure-Activity Relationship |
|
dc.subject |
Dose-Response Relationship, Drug |
|
dc.subject |
Ether-A-Go-Go Potassium Channels |
|
dc.subject |
Diarylquinolines |
|
dc.subject |
CFU, colony-forming units |
|
dc.subject |
HPLC, high-performance liquid chromatography |
|
dc.subject |
LDA, lithium diisopropylamide |
|
dc.subject |
LORA, low oxygen recovery assay |
|
dc.subject |
LiTMP, lithium tetramethylpiperidide |
|
dc.subject |
M. tb, mycobacterium tuberculosis |
|
dc.subject |
MABA, microplate alamar blue assay |
|
dc.subject |
MDR, multidrug-resistant |
|
dc.subject |
MIC90, minimum concentration for 90% inhibition of growth |
|
dc.subject |
TB, tuberculosis |
|
dc.subject |
hERG (human Ether-a-go-go Related Gene) |
|
dc.subject |
Antitubercular Agents |
|
dc.subject |
Diarylquinolines |
|
dc.subject |
Dose-Response Relationship, Drug |
|
dc.subject |
Ether-A-Go-Go Potassium Channels |
|
dc.subject |
Humans |
|
dc.subject |
Microbial Sensitivity Tests |
|
dc.subject |
Molecular Structure |
|
dc.subject |
Mycobacterium tuberculosis |
|
dc.subject |
Potassium Channel Blockers |
|
dc.subject |
Pyridines |
|
dc.subject |
Structure-Activity Relationship |
|
dc.subject |
Science & Technology |
|
dc.subject |
Life Sciences & Biomedicine |
|
dc.subject |
Physical Sciences |
|
dc.subject |
Biochemistry & Molecular Biology |
|
dc.subject |
Chemistry, Medicinal |
|
dc.subject |
Chemistry, Organic |
|
dc.subject |
Pharmacology & Pharmacy |
|
dc.subject |
Chemistry |
|
dc.subject |
CFU, colony-forming units |
|
dc.subject |
hERG (human Ether-a-go-go Related Gene) |
|
dc.subject |
HPLC, high-performance liquid |
|
dc.subject |
chromatography LDA, lithium diisopropylamide |
|
dc.subject |
LiTMP, lithium tetramethylpiperidide |
|
dc.subject |
LORA, low oxygen recovery assay |
|
dc.subject |
MABA, microplate alamar blue assay |
|
dc.subject |
MDR, multidrug-resistant |
|
dc.subject |
MIC90, minimum concentration for 90% |
|
dc.subject |
inhibition of growth |
|
dc.subject |
M. tb, mycobacterium tuberculosis |
|
dc.subject |
TB, tuberculosis |
|
dc.subject |
TUBERCULOSIS DRUG BEDAQUILINE |
|
dc.subject |
DIARYLQUINOLINES |
|
dc.subject |
ASSAY |
|
dc.subject |
1115 Pharmacology and Pharmaceutical Sciences |
|
dc.subject |
Biomedical |
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dc.subject |
Basic Science |
|
dc.subject |
Orphan Drug |
|
dc.subject |
Rare Diseases |
|
dc.subject |
Tuberculosis |
|
dc.subject |
Cardiovascular |
|
dc.subject |
Heart Disease |
|
dc.subject |
Cardiovascular |
|
dc.subject |
5.1 Pharmaceuticals |
|
dc.subject |
0304 Medicinal and Biomolecular Chemistry |
|
dc.subject |
0305 Organic Chemistry |
|
dc.subject |
1115 Pharmacology and Pharmaceutical Sciences |
|
dc.title |
3,5-Dialkoxypyridine analogues of bedaquiline are potent antituberculosis agents with minimal inhibition of the hERG channel. |
|
dc.type |
Journal Article |
|
dc.identifier.doi |
10.1016/j.bmc.2019.02.026 |
|
pubs.issue |
7 |
|
pubs.begin-page |
1292 |
|
pubs.volume |
27 |
|
dc.date.updated |
2022-01-10T01:08:34Z |
|
dc.rights.holder |
Copyright: The authors |
en |
pubs.author-url |
https://www.ncbi.nlm.nih.gov/pubmed/30803745 |
|
pubs.end-page |
1307 |
|
pubs.publication-status |
Published |
|
dc.rights.accessrights |
http://purl.org/eprint/accessRights/OpenAccess |
en |
pubs.subtype |
Research Support, Non-U.S. Gov't |
|
pubs.subtype |
research-article |
|
pubs.subtype |
Research Support, U.S. Gov't, Non-P.H.S. |
|
pubs.subtype |
Journal Article |
|
pubs.elements-id |
764067 |
|
dc.identifier.eissn |
1464-3391 |
|
dc.identifier.pii |
S0968-0896(18)31745-0 |
|