Identification of pyrazine-based TrkA inhibitors: Design, synthesis, evaluation, and computational modeling studies

Brendan Frett, Nick McConnell, Yuanxiang Wang, Zhigang Xu, Andrew Ambrose, Hong Yu Li

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Trk receptors play a key role in the development and maintenance of neuronal networks. Recent evidence suggests that the Trk family, specifically TrkA, is an important driver for tumour growth, inflammatory and neuropathic pain, and chemoresistance. Through a computational screen, a novel Trk active pharmacophore was identified and a series of pyrazine-based inhibitors were developed, which potently inhibited TrkA. Inhibitors displayed the highest activity on TrkA when screened against a small, tyrosine kinase panel and also exhibited a non-linear SAR. Predicted binding modes of the inhibitors were examined, which identified exploitable regions for future development of more advanced inhibitors. This journal is

Original languageEnglish (US)
Pages (from-to)1507-1514
Number of pages8
JournalMedChemComm
Volume5
Issue number10
DOIs
StatePublished - Oct 1 2014

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry

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