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

Bioorganic & Medicinal Chemistry
Sarjubhai PatelNicholas R Natale

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.

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Citations

Feb 2, 2013·Canadian Journal of Physiology and Pharmacology·Robert G UngardGurmit Singh
Mar 13, 2012·Expert Opinion on Investigational Drugs·Harald Sontheimer, Richard J Bridges
May 14, 2011·British Journal of Pharmacology·Richard J BridgesSarjubhai A Patel
May 17, 2012·Acta Crystallographica. Section E, Structure Reports Online·Jun-Tao ZhaoJu Zhu
Dec 5, 2020·Future Medicinal Chemistry·Oya Unsal Tan, Keriman Ozadali Sari
Feb 20, 2021·Neurochemical Research·Ekaitz Errasti-Murugarren, Manuel Palacín
Aug 26, 2018·Bioorganic & Medicinal Chemistry·Christina GatesN R Natale

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