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

Show simple item record

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

Files in this item

There are no files associated with this item.

Find Full text

This item appears in the following Collection(s)

Show simple item record


Search ResearchSpace