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.
- 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: [email protected].
- 2. NTNU, Norwegian University of Science and Technology, Department of Chemistry, Høgskoleringen 5, NO-7491 Trondheim, Norway. Electronic address: [email protected].
- 3. NTNU, Norwegian University of Science and Technology, Department of Chemistry, Høgskoleringen 5, NO-7491 Trondheim, Norway. Electronic address: [email protected].
- 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: [email protected].
- 5. NTNU, Norwegian University of Science and Technology, Institute of Chemistry and Material Technology, Faculty of Technology, NTNU, 7491 Trondheim, Norway. Electronic address: [email protected].
- 6. NTNU, Norwegian University of Science and Technology, Department of Chemistry, Høgskoleringen 5, NO-7491 Trondheim, Norway. Electronic address: [email protected].
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.