2. Academic Validation
  3. 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

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

  • J Med Chem. 2016 Sep 8;59(17):8103-24. doi: 10.1021/acs.jmedchem.6b00883.
Jeff B Smaill 1 2,  Andrea J Gonzales 3,  Julie A Spicer 1 2,  Helen Lee 3,  Jessica E Reed 3,  Karen Sexton 3,  Irene W Althaus 3,  Tong Zhu 3,  Shannon L Black 1,  Adrian Blaser 1,  William A Denny 1 2,  Paul A Ellis 3,  Stephen Fakhoury 3,  Patricia J Harvey 3,  Ken Hook 3,  Florence O J McCarthy 1,  Brian D Palmer 1 2,  Freddy Rivault 1,  Kevin Schlosser 3,  Teresa Ellis 3,  Andrew M Thompson 1,  Erin Trachet 3,  R Thomas Winters 3,  Haile Tecle 3,  Alexander Bridges 3
Affiliations

Affiliations

  • 1 Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland , Private Bag 92019, Auckland 1142, New Zealand.
  • 2 Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland , Private Bag 92019, Auckland 1142, New Zealand.
  • 3 Pfizer Global Research and Development, Michigan Laboratories , 2800 Plymouth Road, Ann Arbor, Michigan 48105-1047, United States.
PMID: 27491023 DOI: 10.1021/acs.jmedchem.6b00883
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.

Figures