dc.contributor.author |
Blaser, Adrian |
en |
dc.contributor.author |
Palmer, Brian |
en |
dc.contributor.author |
Sutherland, Hamish |
en |
dc.contributor.author |
Kmentova, I |
en |
dc.contributor.author |
Franzblau, SG |
en |
dc.contributor.author |
Wan, B |
en |
dc.contributor.author |
Wang, Y |
en |
dc.contributor.author |
Ma, Z |
en |
dc.contributor.author |
Thompson, Andrew |
en |
dc.contributor.author |
Denny, William |
en |
dc.coverage.spatial |
United States |
en |
dc.date.accessioned |
2012-03-12T01:00:55Z |
en |
dc.date.issued |
2012 |
en |
dc.identifier.citation |
J Med Chem 55(1):312-326 12 Jan 2012 |
en |
dc.identifier.issn |
0022-2623 |
en |
dc.identifier.uri |
http://hdl.handle.net/2292/13801 |
en |
dc.description.abstract |
Analogues of clinical tuberculosis drug (6S)-2-nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (PA-824), in which the OCH(2) linkage was replaced with amide, carbamate, and urea functionality, were investigated as an alternative approach to address oxidative metabolism, reduce lipophilicity, and improve aqueous solubility. Several soluble monoaryl examples displayed moderately improved (∼2- to 4-fold) potencies against replicating Mycobacterium tuberculosis but were generally inferior inhibitors under anaerobic (nonreplicating) conditions. More lipophilic biaryl derivatives mostly displayed similar or reduced potencies to these in contrast to the parent biaryl series. The leading biaryl carbamate demonstrated exceptional metabolic stability and a 5-fold better efficacy than the parent drug in a mouse model of acute M. tuberculosis infection but was poorly soluble. Bioisosteric replacement of this biaryl moiety by arylpiperazine resulted in a soluble, orally bioavailable carbamate analogue providing identical activity in the acute model, comparable efficacy to OPC-67683 in a chronic infection model, favorable pharmacokinetic profiles across several species, and enhanced safety. |
en |
dc.language |
eng |
en |
dc.publisher |
American Chemical Society |
en |
dc.relation.ispartofseries |
Journal of Medicinal Chemistry |
en |
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. Details obtained from http://www.sherpa.ac.uk/romeo/issn/0022-2623/ |
en |
dc.rights.uri |
https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm |
en |
dc.title |
Structure-activity relationships for amide-, carbamate-, and urea-linked analogues of the tuberculosis drug (6S)-2-nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (PA-824) |
en |
dc.type |
Journal Article |
en |
dc.identifier.doi |
10.1021/jm2012276 |
en |
pubs.issue |
1 |
en |
pubs.begin-page |
312 |
en |
pubs.volume |
55 |
en |
dc.rights.holder |
Copyright: American Chemical Society |
en |
dc.identifier.pmid |
22148391 |
en |
pubs.author-url |
http://pubs.acs.org/doi/abs/10.1021/jm2012276 |
en |
pubs.end-page |
326 |
en |
dc.rights.accessrights |
http://purl.org/eprint/accessRights/RestrictedAccess |
en |
pubs.subtype |
Article |
en |
pubs.elements-id |
267500 |
en |
pubs.org-id |
Medical and Health Sciences |
en |
pubs.org-id |
Medical Sciences |
en |
pubs.org-id |
Auckland Cancer Research |
en |
pubs.org-id |
Science |
en |
pubs.org-id |
Science Research |
en |
pubs.org-id |
Maurice Wilkins Centre (2010-2014) |
en |
dc.identifier.eissn |
1520-4804 |
en |
pubs.record-created-at-source-date |
2012-02-20 |
en |