title: Isoxazole analogues bind the system xc- transporter: structure-activity relationship and pharmacophore model.
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.
authors.affiliation: NIH COBRE Center for Structural and Functional Neuroscience, The University of Montana, Missoula, MT 59812, USA.
authors.forename: Sarjubhai A
authors.initials: SA
authors.lastname: Patel
authors.forename: Trideep
authors.initials: T
authors.lastname: Rajale
authors.forename: Erin
authors.initials: E
authors.lastname: O'Brien
authors.forename: David J
authors.initials: DJ
authors.lastname: Burkhart
authors.forename: Jared K
authors.initials: JK
authors.lastname: Nelson
authors.forename: Brendan
authors.initials: B
authors.lastname: Twamley
authors.forename: Alex
authors.initials: A
authors.lastname: Blumenfeld
authors.forename: Monika I
authors.initials: MI
authors.lastname: Szabon-Watola
authors.forename: John M
authors.initials: JM
authors.lastname: Gerdes
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Bridges
authors.forename: Nicholas R
authors.initials: NR
authors.lastname: Natale
mesh_terms: D027182:Amino Acid Transport System y+ / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D000596:Amino Acids / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability / Q000187:drug effects*; D018360:Crystallography, X-Ray; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D006835:Hydrazones / Q000737:chemistry / Q000494:pharmacology; D007555:Isoxazoles / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D013329:Structure-Activity Relationship
chemical_list: D027182:Amino Acid Transport System y+; D000596:Amino Acids; D006835:Hydrazones; D007555:Isoxazoles; C118895:SLC7A11 protein, human; D018698:Glutamic Acid