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. Epub 2016 Aug 22.

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.

MeSH terms

  • Administration, Oral
  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology
  • Dogs
  • ErbB Receptors / antagonists & inhibitors*
  • 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
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Morpholines
  • Pyridines
  • Pyrimidines
  • Quinazolines
  • Quinazolinones
  • dacomitinib
  • Canertinib
  • ErbB Receptors