학술논문
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.
Document Type
Article
Author
Smaill, Jeff B.; Gonzales, Andrea J.; Spicer, Julie A.; Lee, Helen; Reed, Jessica E.; Sexton, Karen; Althaus, Irene W.; Tong Zhu; 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
Source
Subject
*PROTEIN-tyrosine kinase inhibitors
*QUINAZOLINE
*PYRIMIDINE derivatives
*EPIDERMAL growth factor receptors
*STRUCTURE-activity relationship in pharmacology
*DRUG stability
*PHARMACOKINETICS
*THERAPEUTICS
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Language
ISSN
0022-2623
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. [ABSTRACT FROM AUTHOR]