Abstract
A noninvasive topical ocular therapy for the treatment of neovascular or "wet" age-related macular degeneration would provide a patient administered alternative to the current standard of care, which requires physician administered intravitreal injections. This manuscript describes a novel strategy for the use of in vivo models of choroidal neovascularization (CNV) as the primary means of developing SAR related to efficacy from topical administration. Ultimately, this effort led to the discovery of acrizanib (LHA510), a small-molecule VEGFR-2 inhibitor with potency and efficacy in rodent CNV models, limited systemic exposure after topical ocular administration, multiple formulation options, and an acceptable rabbit ocular PK profile.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Administration, Topical*
-
Animals
-
Choroidal Neovascularization
-
Drug Discovery
-
Indoles / administration & dosage*
-
Indoles / pharmacokinetics
-
Indoles / therapeutic use
-
Ophthalmic Solutions
-
Protein Kinase Inhibitors
-
Pyrazoles / administration & dosage*
-
Pyrazoles / pharmacokinetics
-
Pyrazoles / therapeutic use
-
Pyrimidines / administration & dosage*
-
Pyrimidines / pharmacokinetics
-
Pyrimidines / therapeutic use
-
Rabbits
-
Rodentia
-
Structure-Activity Relationship
-
Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
-
Wet Macular Degeneration / drug therapy*
Substances
-
Indoles
-
Ophthalmic Solutions
-
Protein Kinase Inhibitors
-
Pyrazoles
-
Pyrimidines
-
Vascular Endothelial Growth Factor Receptor-2
-
acrizanib