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

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 c...

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Published in:Journal of medicinal chemistry 2016-09, Vol.59 (17), p.8103-8124
Main Authors: Smaill, Jeff B, Gonzales, Andrea J, Spicer, Julie A, Lee, Helen, Reed, Jessica E, Sexton, Karen, Althaus, Irene W, Zhu, Tong, Black, Shannon L, Blaser, Adrian, Denny, William A, Ellis, Paul A, Fakhoury, Stephen, Harvey, Patricia J, Hook, Ken, McCarthy, Florence O. J, Palmer, Brian D, Rivault, Freddy, Schlosser, Kevin, Ellis, Teresa, Thompson, Andrew M, Trachet, Erin, Winters, R. Thomas, Tecle, Haile, Bridges, Alexander
Format: Article
Language:English
Subjects:
Administration, Oral
Animals
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacokinetics
Antineoplastic Agents - pharmacology
Dogs
Heterografts
Humans
Injections, Intravenous
Macaca fascicularis
Male
Mice, Nude
Morpholines - chemical synthesis
Morpholines - chemistry
Morpholines - pharmacokinetics
Morpholines - pharmacology
Neoplasm Transplantation
Phosphorylation
Pyridines - chemical synthesis
Pyridines - chemistry
Pyridines - pharmacokinetics
Pyridines - pharmacology
Pyrimidines - chemical synthesis
Pyrimidines - chemistry
Pyrimidines - pharmacokinetics
Pyrimidines - pharmacology
Quinazolines - chemical synthesis
Quinazolines - chemistry
Quinazolines - pharmacokinetics
Quinazolines - pharmacology
Quinazolinones - chemical synthesis
Quinazolinones - chemistry
Quinazolinones - pharmacokinetics
Quinazolinones - pharmacology
Rats, Sprague-Dawley
Receptor, Epidermal Growth Factor - antagonists & inhibitors
Stereoisomerism
Structure-Activity Relationship
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.6b00883