dc.contributor.author |
Hay, Michael |
en |
dc.contributor.author |
Hicks, Kevin |
en |
dc.contributor.author |
Pruijn, Frederik |
en |
dc.contributor.author |
Pchalek, K |
en |
dc.contributor.author |
Siim, Bronwyn |
en |
dc.contributor.author |
Wilson, William |
en |
dc.contributor.author |
Denny, William |
en |
dc.date.accessioned |
2011-11-17T17:23:50Z |
en |
dc.date.issued |
2007 |
en |
dc.identifier.citation |
Journal of Medicinal Chemistry 50(25):6392-6404 2007 |
en |
dc.identifier.issn |
0022-2623 |
en |
dc.identifier.uri |
http://hdl.handle.net/2292/9254 |
en |
dc.description.abstract |
Pharmacokinetic/pharmacodynamic (PK/PD) modeling has shown the antitumor activity of tirapazamine (TPZ), a bioreductive hypoxia-selective cytotoxin, to be limited by poor penetration through hypoxic tumor tissue. We have prepared a series of 1,2,4-benzotriazine 1,4-dioxide (BTO) analogues of TPZ to improve activity against hypoxic cells by increasing extravascular transport. The 6 substituents modified lipophilicity and rates of hypoxic metabolism. 3-Alkylamino substituents increased aqueous solubility and also influenced lipophilicity and hypoxic metabolism. PK/PD model-guided screening was used to select six BTOs for evaluation against hypoxic cells in HT29 human tumor xenografts. All six BTOs were active in vivo, and two provided greater hypoxic cell killing than TPZ because of improved transport and/or plasma PK. This PK/PD model considers two causes of therapeutic failure (limited tumor penetration and poor plasma pharmacokinetics) often not addressed early in drug development and provides a general strategy for selecting candidates for in vivo evaluation during lead optimization. |
en |
dc.language |
EN |
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.subject |
MULTICELLULAR LAYER CULTURES |
en |
dc.subject |
PREDICTS RADIATION RESPONSE |
en |
dc.subject |
ONE-ELECTRON REDUCTION |
en |
dc.subject |
PHASE-II TRIAL |
en |
dc.subject |
BIOREDUCTIVE DRUGS |
en |
dc.subject |
TUMOR HYPOXIA |
en |
dc.subject |
DNA-DAMAGE |
en |
dc.subject |
OXYGEN DEPENDENCE |
en |
dc.subject |
ANTICANCER-DRUG |
en |
dc.subject |
CANCER-THERAPY |
en |
dc.title |
Pharmacokinetic/pharmacodynamic model-guided identification of hypoxia-selective 1,2,4-benzotriazine 1,4-dioxides with antitumor activity: the role of extravascular transport |
en |
dc.type |
Journal Article |
en |
dc.identifier.doi |
10.1021/jm070670g |
en |
pubs.issue |
25 |
en |
pubs.begin-page |
6392 |
en |
pubs.volume |
50 |
en |
dc.rights.holder |
Copyright: American Chemical Society |
en |
dc.identifier.pmid |
18001018 |
en |
pubs.end-page |
6404 |
en |
dc.rights.accessrights |
http://purl.org/eprint/accessRights/RestrictedAccess |
en |
pubs.subtype |
Article |
en |
pubs.elements-id |
74423 |
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 |
Pathology |
en |
pubs.org-id |
Science |
en |
pubs.org-id |
Science Research |
en |
pubs.org-id |
Maurice Wilkins Centre (2010-2014) |
en |
pubs.record-created-at-source-date |
2010-09-01 |
en |
pubs.dimensions-id |
18001018 |
en |