Peer-Reviewed Journal Details
Mandatory Fields
Smaill JB;Gonzales AJ;Spicer JA;Lee H;Reed JE;Sexton K;Althaus IW;Zhu T;Black SL;Blaser A;Denny WA;Ellis PA;Fakhoury S;Harvey PJ;Hook K;McCarthy FO;Palmer BD;Rivault F;Schlosser K;Ellis T;Thompson AM;Trachet E;Winters RT;Tecle H;Bridges A;
2016
August
Journal of Medicinal Chemistry
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.
Validated
Optional Fields
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.
1520-4804
10.1021/acs.jmedchem.6b00883
Grant Details