Tyrosine kinase inhibitors. 19. 6-Alkynamides of 4-anilinoquinazolines and 4-anilinopyrido[3,4-d]pyrimidines as irreversible inhibitors of the erbB family of tyrosine kinase receptors

J Med Chem. 2006 Feb 23;49(4):1475-85. doi: 10.1021/jm050936o.

Abstract

Structure-activity relationships for inhibition of erbB1, erbB2, and erbB4 were determined for a series of alkynamide analogues of quinazoline- and pyrido[3,4-d]pyrimidine-based compounds. The compounds were prepared by coupling the appropriate 6-aminoquinazolines or 6-aminopyrido[3,4-d]pyrimidines with alkynoic acids, using EDCI.HCl in pyridine. The compounds showed pan-erbB enzyme inhibition but were on average about 10-fold more potent against erbB1 than against erbB2 and erbB4. For cellular inhibition, the nature of the alkylating side chains was an important determinant, with 5-dialkylamino-2-pentynamide type Michael acceptors providing the highest potency. This is suggested to be due to an improved ability of the amine to participate in an autocatalysis of the Michael reaction with enzyme cysteine residues. Pyrido[3,4-d]pyrimidine analogue 39 was selected for in vivo evaluation and achieved tumor regressions at 10 mg/kg in the A431 human epidermoid carcinoma and at 40 mg/kg for the SF767 human glioblastoma and the SKOV3 human ovarian carcinoma. Complete stasis was observed at 40 mg/kg in the BXPC3 human pancreatic carcinoma as well as in the H125 human non-small-cell lung carcinoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkynes / chemical synthesis*
  • Alkynes / chemistry
  • Alkynes / pharmacology
  • Amides / chemical synthesis*
  • Amides / chemistry
  • Amides / pharmacokinetics
  • Amides / pharmacology
  • Aniline Compounds / chemical synthesis
  • Aniline Compounds / chemistry
  • Aniline Compounds / pharmacokinetics
  • Aniline Compounds / pharmacology
  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology
  • Cell Line
  • Dogs
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / metabolism
  • Haplorhini
  • Humans
  • Mice
  • Mice, Nude
  • Mice, SCID
  • Phosphorylation
  • Pyrimidines / chemical synthesis*
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacokinetics
  • Pyrimidines / pharmacology
  • Quinazolines / chemical synthesis*
  • Quinazolines / chemistry
  • Quinazolines / pharmacokinetics
  • Quinazolines / pharmacology
  • Rats
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Receptor, ErbB-2 / antagonists & inhibitors
  • Receptor, ErbB-2 / metabolism
  • Receptor, ErbB-4
  • Structure-Activity Relationship
  • Xenograft Model Antitumor Assays

Substances

  • Alkynes
  • Amides
  • Aniline Compounds
  • Antineoplastic Agents
  • Pyrimidines
  • Quinazolines
  • ERBB4 protein, human
  • ErbB Receptors
  • Erbb4 protein, mouse
  • Erbb4 protein, rat
  • Receptor Protein-Tyrosine Kinases
  • Receptor, ErbB-2
  • Receptor, ErbB-4