dc.contributor.author |
Thompson, Andrew M |
|
dc.contributor.author |
O’Connor, Patrick D |
|
dc.contributor.author |
Marshall, Andrew J |
|
dc.contributor.author |
Yardley, Vanessa |
|
dc.contributor.author |
Maes, Louis |
|
dc.contributor.author |
Gupta, Suman |
|
dc.contributor.author |
Launay, Delphine |
|
dc.contributor.author |
Braillard, Stephanie |
|
dc.contributor.author |
Chatelain, Eric |
|
dc.contributor.author |
Wan, Baojie |
|
dc.contributor.author |
Franzblau, Scott G |
|
dc.contributor.author |
Ma, Zhenkun |
|
dc.contributor.author |
Cooper, Christopher B |
|
dc.contributor.author |
Denny, William A |
|
dc.date.accessioned |
2020-12-08T23:52:36Z |
|
dc.date.available |
2020-12-08T23:52:36Z |
|
dc.date.issued |
2020-10-1 |
|
dc.identifier.citation |
European journal of medicinal chemistry 112914 10 Oct 2020 |
|
dc.identifier.issn |
0223-5234 |
|
dc.identifier.uri |
http://hdl.handle.net/2292/53944 |
|
dc.description.abstract |
© 2020 Elsevier Masson SAS Previous investigation of the potent antileishmanial properties of antitubercular 7-substituted 2-nitroimidazo[2,1-b][1,3]oxazines with biaryl side chains led to our development of a new clinical candidate for visceral leishmaniasis (DNDI-0690). Within a collaborative backup program, a racemic monoaryl lead (3) possessing comparable activity in mice but a greater hERG liability formed the starting point for our pursuit of efficacious second generation analogues having good solubility and safety. Asymmetric synthesis and appraisal of its enantiomers first established that chiral preferences for in vivo efficacy were species dependent and that neither form afforded a reduced hERG risk. However, in line with our findings in a structurally related series, less lipophilic heteroaryl ethers provided significant solubility enhancements (up to 16-fold) and concomitantly attenuated hERG inhibition. One promising pyridine derivative (49) displayed 100% oral bioavailability in mice and delivered a 96% parasite burden reduction when dosed at 50 mg/kg in a Leishmania donovani mouse model of visceral leishmaniasis. |
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dc.language |
en |
|
dc.publisher |
Elsevier BV |
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dc.relation.ispartofseries |
European Journal of Medicinal Chemistry |
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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-nc-nd/4.0/ |
|
dc.subject |
0304 Medicinal and Biomolecular Chemistry |
|
dc.subject |
0305 Organic Chemistry |
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dc.subject |
1115 Pharmacology and Pharmaceutical Sciences |
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dc.title |
Heteroaryl ether analogues of an antileishmanial 7-substituted 2-nitroimidazooxazine lead afford attenuated hERG risk: in vitro and in vivo appraisal |
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dc.type |
Journal Article |
|
dc.identifier.doi |
10.1016/j.ejmech.2020.112914 |
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pubs.begin-page |
112914 |
|
dc.date.updated |
2020-11-17T20:25:41Z |
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dc.rights.holder |
Copyright: Elsevier |
en |
pubs.publication-status |
Published |
|
dc.rights.accessrights |
http://purl.org/eprint/accessRights/OpenAccess |
en |
pubs.subtype |
Journal Article |
|
pubs.elements-id |
823477 |
|
dc.identifier.eissn |
1768-3254 |
|
pubs.number |
112914 |
|