Isoxazole analogues bind the System xc- transporter: Structure-activity relationship and pharmacophore model

Sarjubhai A. Patel, Trideep Rajale, Erin O'Brien, David J. Burkhart, Jared K. Nelson, Brendan Twamley, Alex Blumenfeld, Monika I. Szabon-Watola, John M. Gerdes, Richard J. Bridges, Nicholas R. Natale

Research output: Contribution to journalArticlepeer-review

Abstract

Analogues of amino methylisoxazole propionic acid (AMPA), were prepared from a common intermediate 12, including lipophilic analogues using lateral metalation and electrophilic quenching, and were evaluated at System xc-. Both the 5-naphthylethyl-(16) and 5-naphthylmethoxymethyl-(17) analogues adopt an E-conformation in the solid state, yet while the former has robust binding at System xc-, the latter is virtually devoid of activity. The most potent analogues were amino acid naphthyl-ACPA 7g, and hydrazone carboxylic acid, 11e Y = Y′ = 3,5-(CF3)2, which both inhibited glutamate uptake by the System xc- transporter with comparable potency to the endogenous substrate cystine, whereas in contrast the closed isoxazolo[3,4-d] pyridazinones 13 have significantly lower activity. A preliminary pharmacophore model has been constructed to provide insight into the analogue structure-activity relationships.

Original languageEnglish
Pages (from-to)202-213
Number of pages12
JournalBioorganic and Medicinal Chemistry
Volume18
Issue number1
DOIs
StatePublished - Jan 1 2010

Keywords

  • Isoxazole
  • Pharmacophore
  • Structure-activity relationship
  • System x
  • Transporter

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