Chiral 6-aryl-furo[2,3-d]pyrimidin-4-amines as EGFR inhibitors

Jin Han; Svein Jacob Kaspersen; Sondre Nervik; Kristin G Nørsett; Eirik Sundby; Bård Helge Hoff

doi:10.1016/j.ejmech.2016.04.054

Chiral 6-aryl-furo[2,3-d]pyrimidin-4-amines as EGFR inhibitors

Eur J Med Chem. 2016 Aug 25:119:278-99. doi: 10.1016/j.ejmech.2016.04.054. Epub 2016 Apr 25.

Authors

Jin Han¹, Svein Jacob Kaspersen², Sondre Nervik³, Kristin G Nørsett⁴, Eirik Sundby⁵, Bård Helge Hoff⁶

Affiliations

¹ NTNU, Norwegian University of Science and Technology, Department of Chemistry, Høgskoleringen 5, NO-7491 Trondheim, Norway; NTNU, Norwegian University of Science and Technology, Institute of Chemistry and Material Technology, Faculty of Technology, NTNU, 7491 Trondheim, Norway. Electronic address: Jin.Han@ntnu.no.
² NTNU, Norwegian University of Science and Technology, Department of Chemistry, Høgskoleringen 5, NO-7491 Trondheim, Norway. Electronic address: Svein.Jacob.Kaspersen@chem.ntnu.no.
³ NTNU, Norwegian University of Science and Technology, Department of Chemistry, Høgskoleringen 5, NO-7491 Trondheim, Norway. Electronic address: Sondre.Nervik@ntnu.no.
⁴ NTNU, Norwegian University of Science and Technology, Department of Cancer Research and Molecular Medicine, Prinsesse Kristinas gt. 1, N-7030 Trondheim, Norway. Electronic address: Kristin.Norsett@ntnu.no.
⁵ NTNU, Norwegian University of Science and Technology, Institute of Chemistry and Material Technology, Faculty of Technology, NTNU, 7491 Trondheim, Norway. Electronic address: Sundby@hist.no.
⁶ NTNU, Norwegian University of Science and Technology, Department of Chemistry, Høgskoleringen 5, NO-7491 Trondheim, Norway. Electronic address: Bard.Helge.Hoff@chem.ntnu.no.

PMID: 27235841
DOI: 10.1016/j.ejmech.2016.04.054

Abstract

Epidermal growth factor receptor inhibitors are of importance in cancer therapy and possibly in the management of pain. Herein, we report a structure-activity relationship study with 29 new 6-aryl-furo[2,3-d]pyrimidin-4-amines, involving modification of the 4-amino group and 6-aryl function. The EGFR activity was especially dependent on having a chiral 4-benzylamino group with correct stereochemistry. Molecular dynamics indicate this to be due to favourable cation-π interactions. The most active inhibitor identified, equipotent to Erlotinib, was substituted with (R)-1-phenylethylamine at C-4 and a N(1), N(1)-dimethyl-1,2-diamine group in para position of the 6-aryl moiety. These new furopyrimidines had a different off-target kinase profile when compared to Erlotinib, and also possessed high activity towards Ba/F3 EGFR(L858R) reporter cells. Further, comparing the EGFR data of the furo[2,3-d]pyrimidin-4-amines with that of the corresponding thieno- and pyrrolopyrimidines concludes the furopyrimidine scaffold to be highly useful for development of new epidermal growth factor receptor antagonists.

Keywords: Chiral drug; EGFR; Erlotinib; Furopyrimidine; Kinase.

MeSH terms

Amines / chemistry*
ErbB Receptors / antagonists & inhibitors*
ErbB Receptors / chemistry
ErbB Receptors / metabolism
Inhibitory Concentration 50
Kinetics
Molecular Docking Simulation
Protein Conformation
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / metabolism
Protein Kinase Inhibitors / pharmacology*
Pyrimidines / chemical synthesis
Pyrimidines / chemistry*
Pyrimidines / metabolism
Pyrimidines / pharmacology*
Stereoisomerism
Structure-Activity Relationship

Substances

Amines
Protein Kinase Inhibitors
Pyrimidines
ErbB Receptors