dc.contributor.author |
Smaill, Jeffrey |
en |
dc.contributor.author |
Gonzales, AJ |
en |
dc.contributor.author |
Spicer, Julie |
en |
dc.contributor.author |
Lee, H |
en |
dc.contributor.author |
Reed, JE |
en |
dc.contributor.author |
Sexton, K |
en |
dc.contributor.author |
Althaus, IW |
en |
dc.contributor.author |
Zhu, T |
en |
dc.contributor.author |
Black, Shannon |
en |
dc.contributor.author |
Blaser, Adrian |
en |
dc.contributor.author |
Denny, William |
en |
dc.contributor.author |
Ellis, PA |
en |
dc.contributor.author |
Fakhoury, S |
en |
dc.contributor.author |
Harvey, PJ |
en |
dc.contributor.author |
Hook, K |
en |
dc.contributor.author |
McCarthy, FOJ |
en |
dc.contributor.author |
Palmer, Brian |
en |
dc.contributor.author |
Rivault, F |
en |
dc.contributor.author |
Schlosser, K |
en |
dc.contributor.author |
Ellis, T |
en |
dc.contributor.author |
Thompson, Andrew |
en |
dc.contributor.author |
Trachet, E |
en |
dc.contributor.author |
Winters, RT |
en |
dc.contributor.author |
Tecle, H |
en |
dc.contributor.author |
Bridges, A |
en |
dc.date.accessioned |
2017-04-06T04:21:29Z |
en |
dc.date.issued |
2016-09-08 |
en |
dc.identifier.citation |
Journal of Medicinal Chemistry 59(17):8103-8124 08 Sep 2016 |
en |
dc.identifier.issn |
0022-2623 |
en |
dc.identifier.uri |
http://hdl.handle.net/2292/32487 |
en |
dc.description.abstract |
Structure–activity relationships for inhibition of erbB1, erbB2, and erbB4 were determined for a series of quinazoline- and pyrido[3,4-d]pyrimidine-based analogues of the irreversible pan-erbB inhibitor, canertinib. Cyclic amine bearing crotonamides were determined to provide rapid inhibition of cellular erbB1 autophosphorylation and good metabolic stability in liver microsome and hepatocyte assays. The influence of 4-anilino substitution on pan-erbB inhibitory potency was investigated. Several anilines were identified as providing potent, reversible pan-erbB inhibition. Optimum 4- and 6-substituents with known 7-substituents provided preferred irreversible inhibitors for pharmacodynamic testing in vivo. Quinazoline 54 and pyrido[3,4-d]pyrimidine 71 were identified as clearly superior to canertinib. Both compounds possess a piperidinyl crotonamide Michael acceptor and a 3-chloro-4-fluoroaniline, indicating these as optimized 6- and 4-substituents, respectively. Pharmacokinetic comparison of compounds 54 and 71 across three species selected compound 54 as the preferred candidate. Compound 54 (PF-00299804) has been assigned the nomenclature of dacomitinib and is currently under clinical evaluation. |
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. |
en |
dc.rights.uri |
https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm |
en |
dc.title |
Tyrosine Kinase Inhibitors. 20. Optimization of Substituted Quinazoline and Pyrido[3,4- d ]pyrimidine Derivatives as Orally Active, Irreversible Inhibitors of the Epidermal Growth Factor Receptor Family |
en |
dc.type |
Journal Article |
en |
dc.identifier.doi |
10.1021/acs.jmedchem.6b00883 |
en |
pubs.issue |
17 |
en |
pubs.begin-page |
8103 |
en |
pubs.volume |
59 |
en |
dc.rights.holder |
Copyright: American Chemical Society |
en |
dc.identifier.pmid |
27491023 |
en |
pubs.end-page |
8124 |
en |
pubs.publication-status |
Published |
en |
dc.rights.accessrights |
http://purl.org/eprint/accessRights/RestrictedAccess |
en |
pubs.subtype |
Article |
en |
pubs.elements-id |
540043 |
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 |
2017-04-06 |
en |
pubs.dimensions-id |
27491023 |
en |