Truncated structures used in search for new lead compounds and in a retrospective analysis of thienopyrimidine-based EGFR inhibitors

European Journal of Medicinal Chemistry
Steffen BuggeBård Helge Hoff

Abstract

An approach for optimization of epidermal growth factor receptor tyrosine kinase (EGFR-TK) inhibitors using truncated thienopyrimidine structures combined with enzymatic assay has been evaluated. This was done by synthesis and EGFR activity measurement of a series of fragment structures and their corresponding drug-model analogues. On average, the activity of the drug-like structures increased a ten-fold as compared to the fragments. However, the potency of the drug-model compound could not be precisely predicted, visualising the typical challenge with linking substructures. Additionally, the activity data provided useful SAR information with respect to stereochemical preference and the structure requirements of the 4-amino group. A retrospective evaluation of binding efficiency in previously discovered thieno[2,3-d]pyrimidines, suggests a high probability of obtaining potent EGFR inhibitors if based on the 3-chloro-4-fluoroaniline moiety. Compounds derived from (S)-2-hydroxy-1-phenylethylamine also have resulted in highly active EGFR-TK inhibitors. In contrast the 3-ethynylaniline containing structures appears more difficult to develop. Thieno[2,3-d]pyrimidin-4-amines have also been used for construction of irreversible EGFR-T...Continue Reading

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Citations

Nov 26, 2015·European Journal of Medicinal Chemistry·Steffen BuggeBård Helge Hoff
May 29, 2016·European Journal of Medicinal Chemistry·Jin HanBård Helge Hoff
Sep 12, 2016·European Journal of Medicinal Chemistry·Jin HanBård Helge Hoff
Nov 3, 2016·Archiv der Pharmazie·Soha R Abd El HadiKhaled A M Abouzid
Jul 19, 2015·Archives of Pharmacal Research·Chulho LeeGyoonhee Han

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