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)

Show simple item record Blaser, Adrian en Palmer, Brian en Sutherland, Hamish en Kmentova, I en Franzblau, SG en Wan, B en Wang, Y en Ma, Z en Thompson, Andrew en Denny, William en
dc.coverage.spatial United States en 2012-03-12T01:00:55Z en 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 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 en
dc.rights.uri 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 en
pubs.end-page 326 en
dc.rights.accessrights en
pubs.subtype Article en
pubs.elements-id 267500 en Medical and Health Sciences en Medical Sciences en Auckland Cancer Research en Science en Science Research en Maurice Wilkins Centre (2010-2014) en
dc.identifier.eissn 1520-4804 en
pubs.record-created-at-source-date 2012-02-20 en

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