dc.contributor.author |
Blaser, Adrian |
|
dc.contributor.author |
Sutherland, Hamish S |
|
dc.contributor.author |
Tong, Amy ST |
|
dc.contributor.author |
Choi, Peter J |
|
dc.contributor.author |
Conole, Daniel |
|
dc.contributor.author |
Franzblau, Scott G |
|
dc.contributor.author |
Cooper, Christopher B |
|
dc.contributor.author |
Upton, Anna M |
|
dc.contributor.author |
Lotlikar, Manisha |
|
dc.contributor.author |
Denny, William A |
|
dc.contributor.author |
Palmer, Brian D |
|
dc.coverage.spatial |
England |
|
dc.date.accessioned |
2022-01-24T01:24:49Z |
|
dc.date.available |
2022-01-24T01:24:49Z |
|
dc.date.issued |
2019-4 |
|
dc.identifier.citation |
Bioorganic & medicinal chemistry 27(7):1283-1291 Apr 2019 |
|
dc.identifier.issn |
0968-0896 |
|
dc.identifier.uri |
https://hdl.handle.net/2292/58047 |
|
dc.description.abstract |
The ATP-synthase inhibitor bedaquiline is effective against drug-resistant tuberculosis but is extremely lipophilic (clogP 7.25) with a very long plasma half-life. Additionally, inhibition of potassium current through the cardiac hERG channel by bedaquiline, is associated with prolongation of the QT interval, necessitating cardiovascular monitoring. Analogues were prepared where the naphthalene C-unit was replaced with substituted pyridines to produce compounds with reduced lipophilicity, anticipating a reduction in half-life. While there was a direct correlation between in vitro inhibitory activity against M. tuberculosis (MIC<sub>90</sub>) and compound lipophilicity, potency only fell off sharply below a clogP of about 4.0, providing a useful lower bound for analogue design. The bulk of the compounds remained potent inhibitors of the hERG potassium channel, with notable exceptions where IC<sub>50</sub> values were at least 5-fold higher than that of bedaquiline. Many of the compounds had desirably higher rates of clearance than bedaquiline, but this was associated with lower plasma exposures in mice, and similar or higher MICs resulted in lower AUC/MIC ratios than bedaquiline for most compounds. The two compounds with lower potency against hERG exhibited similar clearance to bedaquiline and excellent efficacy in vivo, suggesting further exploration of C-ring pyridyls is worthwhile. |
|
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 |
Animals |
|
dc.subject |
Humans |
|
dc.subject |
Mice |
|
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 |
Bedaquiline |
|
dc.subject |
Bedaquiline analogues |
|
dc.subject |
Drug development |
|
dc.subject |
Lipophilicity |
|
dc.subject |
Tuberculosis |
|
dc.subject |
Animals |
|
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 |
Mice |
|
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 |
MULTIDRUG-RESISTANT TUBERCULOSIS |
|
dc.subject |
DIARYLQUINOLINES |
|
dc.subject |
TMC207 |
|
dc.subject |
ASSAY |
|
dc.subject |
1102 Cardiorespiratory Medicine and Haematology |
|
dc.subject |
Clinical Medicine and Science |
|
dc.subject |
Orphan Drug |
|
dc.subject |
Rare Diseases |
|
dc.subject |
Tuberculosis |
|
dc.subject |
Cardiovascular |
|
dc.subject |
Heart Disease |
|
dc.subject |
Biotechnology |
|
dc.subject |
Cardiovascular |
|
dc.subject |
0304 Medicinal and Biomolecular Chemistry |
|
dc.subject |
0305 Organic Chemistry |
|
dc.subject |
1115 Pharmacology and Pharmaceutical Sciences |
|
dc.title |
Structure-activity relationships for unit C pyridyl analogues of the tuberculosis drug bedaquiline. |
|
dc.type |
Journal Article |
|
dc.identifier.doi |
10.1016/j.bmc.2019.02.025 |
|
pubs.issue |
7 |
|
pubs.begin-page |
1283 |
|
pubs.volume |
27 |
|
dc.date.updated |
2021-12-15T01:33:16Z |
|
dc.rights.holder |
Copyright: The author |
en |
pubs.author-url |
https://www.ncbi.nlm.nih.gov/pubmed/30792104 |
|
pubs.end-page |
1291 |
|
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 |
764068 |
|
dc.identifier.eissn |
1464-3391 |
|
dc.identifier.pii |
S0968-0896(18)31741-3 |
|