Topical administration of a multi-targeted kinase inhibitor suppresses choroidal neovascularization and retinal edema.
Age-related macular degeneration, diabetic retinopathy, and retinal vein occlusions are complicated by neovascularization and macular edema. Multi-targeted kinase inhibitors that inhibit select growth factor receptor tyrosine kinases and/or components of their down-stream signaling cascades (such as Src kinases) are rationale treatment strategies for these disease processes. We describe the discovery and characterization of two such agents. TG100572, which inhibits Src kinases and selected receptor tyrosine kinases, induced apoptosis of proliferating endothelial cells in vitro. Systemic delivery of TG100572 in a murine model of laser-induced choroidal neovascularization (CNV) caused significant suppression of CNV, but with an associated weight loss suggestive of systemic toxicity. To minimize systemic exposure, topical delivery of TG100572 to the cornea was explored, and while substantial levels of TG100572 were achieved in the retina and choroid, superior exposure levels were achieved using TG100801, an inactive prodrug that generates TG100572 by de-esterification. Neither TG100801 nor TG100572 were detectable in plasma following topical delivery of TG100801, and adverse safety signals (such as weight loss) were not observed even with prolonged dosing schedules. Topical TG100801 significantly suppressed laser-induced CNV in mice, and reduced fluorescein leakage from the vasculature and retinal thickening measured by optical coherence tomography in a rat model of retinal vein occlusion. These data suggest that TG100801 may provide a new topically applied treatment approach for ocular neovascularization and retinal edema.
Doukas
John
J
TargeGen, Inc., San Diego, California.
Mahesh
Sankaranarayana
S
Umeda
Naoyasu
N
Kachi
Shu
S
Akiyama
Hideo
H
Yokoi
Katsutoshi
K
Cao
Jon
J
Chen
Zoe
Z
Dellamary
Luis
L
Tam
Betty
B
Racanelli-Layton
Adrienne
A
Hood
John
J
Martin
Michael
M
Noronha
Glenn
G
Soll
Richard
R
Campochiaro
Peter A
PA
D000287:Administration, Topical; D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*; D000818:Animals; D002460:Cell Line; D020256:Choroidal Neovascularization / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D010211:Papilledema / Q000188:drug therapy* / Q000473:pathology; D010636:Phenols / Q000627:therapeutic use*; D011355:Prodrugs / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*; D011817:Rabbits; D051381:Rats; D020318:Rats, Long-Evans; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012160:Retina / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D014227:Triazines / Q000627:therapeutic use*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
C529233:4-chloro-3-(5-methyl-3-((4-(2-pyrrolidin-1-ylethoxy)phenyl)amino)-1,2,4-benzotriazin-7-yl)phenol; D020533:Angiogenesis Inhibitors; D010636:Phenols; D011355:Prodrugs; D047428:Protein Kinase Inhibitors; D014227:Triazines; D020794:Receptor Protein-Tyrosine Kinases; D019061:src-Family Kinases