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.
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.
TargeGen Inc., 9380 Judicial Drive, San Diego California 92121, USA. Palanki@targegen.com
Moorthy S S
MS
Palanki
Elena
E
Dneprovskaia
John
J
Doukas
Richard M
RM
Fine
John
J
Hood
Xinshan
X
Kang
Dan
D
Lohse
Michael
M
Martin
Glenn
G
Noronha
Richard M
RM
Soll
Wolfgang
W
Wrasidlo
Shiyin
S
Yee
Hong
H
Zhu
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D002199:Capillary Permeability / Q000187:drug effects; D049109:Cell Proliferation; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008297:Male; D008958:Models, Molecular; D009203:Myocardial Infarction / Q000150:complications*; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000209:etiology; D010636:Phenols / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D011621:Pteridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011719:Pyrazines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014471:Umbilical Veins / Q000166:cytology; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D000099152:Cadherin 5
D015703:Antigens, CD; D015820:Cadherins; D007527:Isoenzymes; D010636:Phenols; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011621:Pteridines; D011719:Pyrazines; D011725:Pyridines; D042461:Vascular Endothelial Growth Factor A; D000099152:Cadherin 5; C523902:3,3'-(2,4-diaminopteridine-6,7-diyl)diphenol