Isoxazole analogues bind the system xc- transporter: structure-activity relationship and pharmacophore model.
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.
Patel
Sarjubhai A
SA
NIH COBRE Center for Structural and Functional Neuroscience, The University of Montana, Missoula, MT 59812, USA.
Rajale
Trideep
T
O'Brien
Erin
E
Burkhart
David J
DJ
Nelson
Jared K
JK
Twamley
Brendan
B
Blumenfeld
Alex
A
Szabon-Watola
Monika I
MI
Gerdes
John M
JM
Bridges
Richard J
RJ
Natale
Nicholas R
NR
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
D027182:Amino Acid Transport System y+; D000596:Amino Acids; D006835:Hydrazones; D007555:Isoxazoles; C118895:SLC7A11 protein, human; D018698:Glutamic Acid