Format

Send to:

Choose Destination
See comment in PubMed Commons below
Bioorg Med Chem. 2010 Jan 1;18(1):202-13. doi: 10.1016/j.bmc.2009.11.001. Epub 2009 Nov 10.

Isoxazole analogues bind the system xc- transporter: structure-activity relationship and pharmacophore model.

Author information

  • 1NIH COBRE Center for Structural and Functional Neuroscience, The University of Montana, Missoula, MT 59812, USA.

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-(CF(3))(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.

Copyright (c) 2009 Elsevier Ltd. All rights reserved.

PMID:
19932968
[PubMed - indexed for MEDLINE]
PMCID:
PMC2967674
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Elsevier Science Icon for PubMed Central
    Loading ...
    Write to the Help Desk