Synthesis, SAR and unanticipated pharmacological profiles of analogues of the mGluR5 ago-potentiator ADX-47273

Darren W. Engers, Alice L. Rodriguez, Richard Williams, Alexis S. Hammond, Daryl Venable, Oluwatomi Oluwatola, Gary A. Sulikowski, P. Jeffrey Conn, Craig W. Lindsley

Research output: Contribution to journalArticlepeer-review

Abstract

An iterative analogue library synthesis strategy rapidly developed comprehensive SAR for the mGluR5 ago-potentiator ADX-47273. This effort identified key substituents in the 3-position of oxadiazole that engendered either mGluR5 ago-potentiation or pure mGluR5 positive allosteric modulation. The mGluR5 positive allosteric modulators identified possessed the largest fold shifts (up to 27.9-fold) of the glutamate CRC reported to date as well as providing improved physiochemical properties.

Original languageEnglish (US)
Pages (from-to)505-511
Number of pages7
JournalChemMedChem
Volume4
Issue number4
DOIs
StatePublished - Apr 17 2009
Externally publishedYes

Keywords

  • Allosteric modulation
  • Glutamate receptors
  • Neurological agents
  • Structure-activity relationships

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry

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