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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. 2016
Jeff B Smaill, and
Andrea J Gonzales, and
Julie A Spicer, and
Helen Lee, and
Jessica E Reed, and
Karen Sexton, and
Irene W Althaus, and
Tong Zhu, and
Shannon L Black, and
Adrian Blaser, and
William A Denny, and
Paul A Ellis, and
Stephen Fakhoury, and
Patricia J Harvey, and
Ken Hook, and
Florence O J McCarthy, and
Brian D Palmer, and
Freddy Rivault, and
Kevin Schlosser, and
Teresa Ellis, and
Andrew M Thompson, and
Erin Trachet, and
R Thomas Winters, and
Haile Tecle, and
Alexander Bridges
Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland , Private Bag 92019, Auckland 1142, New Zealand.
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.
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Ken Hook, and
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Tong Zhu, and
Shannon L Black, and
Adrian Blaser, and
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Paul A Ellis, and
Stephen Fakhoury, and
Patricia J Harvey, and
Ken Hook, and
Florence O J McCarthy, and
Brian D Palmer, and
Freddy Rivault, and
Kevin Schlosser, and
Teresa Ellis, and
Andrew M Thompson, and
Erin Trachet, and
R Thomas Winters, and
Haile Tecle, and
Alexander Bridges
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Ken Hook, and
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Freddy Rivault, and
Kevin Schlosser, and
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Andrew M Thompson, and
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R Thomas Winters, and
Haile Tecle, and
Alexander Bridges
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Ken Hook, and
Florence O J McCarthy, and
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Tong Zhu, and
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Adrian Blaser, and
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Paul A Ellis, and
Stephen Fakhoury, and
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Ken Hook, and
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Erin Trachet, and
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Haile Tecle, and
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Julie A Spicer, and
Helen Lee, and
Jessica E Reed, and
Karen Sexton, and
Irene W Althaus, and
Tong Zhu, and
Shannon L Black, and
Adrian Blaser, and
William A Denny, and
Paul A Ellis, and
Stephen Fakhoury, and
Patricia J Harvey, and
Ken Hook, and
Florence O J McCarthy, and
Brian D Palmer, and
Freddy Rivault, and
Kevin Schlosser, and
Teresa Ellis, and
Andrew M Thompson, and
Erin Trachet, and
R Thomas Winters, and
Haile Tecle, and
Alexander Bridges
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