Discovery of 3,3'-(2,4-diaminopteridine-6,7-diyl)diphenol as an isozyme-selective inhibitor of PI3K for the treatment of ischemia reperfusion injury associated with myocardial infarction.
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| Abstract |
In studies aimed toward identifying effective and safe inhibitors of kinase signaling cascades that underlie ischemia/reperfusion (I/R) injury, we synthesized a series of pteridines and pyridopyrazines. The design strategy was inspired by the examination of naturally occurring PI3K inhibitors such as wortmannin and quercetin, and building a pharmacophore-based model used for optimization. Structural modifications led to hybrid molecules which incorporated aminopyrimidine and aminopyridine moieties with ATP mimetic characteristics into the pharmacophore motifs to modulate kinase affinity and selectivity. Elaborations involving substitutions of the 2 and 4 positions of the pyrimidine or pyridine ring and the 6 and 7 positions of the central pyrazine ring resulted in in vivo activity profiles which identified potent inhibitors of vascular endothelial growth factor (VEGF) induced vascular leakage. Pathway analysis identified a diaminopteridine-diphenol as a potent and selective phosphatidylinositol-3-kinase (PI3K) inhibitor. The structure-activity relationship studies of various analogues of diaminopteridine-diphenol-based on biochemical assays resulted in potent inhibitors of PI3K.
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| Authors | Moorthy S S Palanki, Elena Dneprovskaia, John Doukas, Richard M Fine, John Hood, Xinshan Kang, Dan Lohse, Michael Martin, Glenn Noronha, Richard M Soll, Wolfgang Wrasidlo, Shiyin Yee, Hong Zhu |
| Journal | Journal of medicinal chemistry (J Med Chem) Vol. 50 Issue 18 Pg. 4279-94 (Sep 06 2007) ISSN: 0022-2623 [Print] United States |
| PMID | 17685602 (Publication Type: Journal Article) |
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