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

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.
Jin Han 1,  Svein Jacob Kaspersen 2,  Sondre Nervik 3,  Kristin G Nørsett 4,  Eirik Sundby 5,  Bård Helge Hoff 6
Affiliations

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.

Figures
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z