title: Chiral 6-aryl-furo[2,3-d]pyrimidin-4-amines as EGFR inhibitors.
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.
authors.affiliation: 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.
authors.forename: Jin
authors.initials: J
authors.lastname: Han
authors.affiliation: NTNU, Norwegian University of Science and Technology, Department of Chemistry, Høgskoleringen 5, NO-7491 Trondheim, Norway. Electronic address: Svein.Jacob.Kaspersen@chem.ntnu.no.
authors.forename: Svein Jacob
authors.initials: SJ
authors.lastname: Kaspersen
authors.affiliation: NTNU, Norwegian University of Science and Technology, Department of Chemistry, Høgskoleringen 5, NO-7491 Trondheim, Norway. Electronic address: Sondre.Nervik@ntnu.no.
authors.forename: Sondre
authors.initials: S
authors.lastname: Nervik
authors.affiliation: 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.
authors.forename: Kristin G
authors.initials: KG
authors.lastname: Nørsett
authors.affiliation: 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.
authors.forename: Eirik
authors.initials: E
authors.lastname: Sundby
authors.affiliation: NTNU, Norwegian University of Science and Technology, Department of Chemistry, Høgskoleringen 5, NO-7491 Trondheim, Norway. Electronic address: Bard.Helge.Hoff@chem.ntnu.no.
authors.forename: Bård Helge
authors.initials: BH
authors.lastname: Hoff
mesh_terms: D000588:Amines / Q000737:chemistry*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D020128:Inhibitory Concentration 50; D007700:Kinetics; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000588:Amines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D066246:ErbB Receptors
keywords: Chiral drug; EGFR; Erlotinib; Furopyrimidine; Kinase