The Discovery of N-(1-Methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-5-((6- ((methylamino)methyl)pyrimidin-4-yl)oxy)-1H-indole-1-carboxamide (Acrizanib), a VEGFR-2 Inhibitor Specifically Designed for Topical Ocular Delivery, as a Therapy for Neovascular Age-Related Macular Degeneration.

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.

• Authors: Christopher M Adams, Karen Anderson, Gerald Artman 3rd, Jean-Claude Bizec, Rosemarie Cepeda, Jason Elliott, Elizabeth Fassbender, Malay Ghosh, Shawn Hanks, Leo A Hardegger, Vinayak P Hosagrahara, Bruce Jaffee, Keith Jendza, Nan Ji, Leland Johnson, Wendy Lee, Donglei Liu, Fang Liu, Debby Long, Fupeng Ma, Nello Mainolfi, Erik L Meredith, Karl Miranda, Yao Peng, Stephen Poor, James Powers, Yubin Qiu, Chang Rao, Siyuan Shen, Jeremy M Sivak, Catherine Solovay, Peter Tarsa, Amber Woolfenden, Chun Zhang, Yiqin Zhang
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 61 Issue 4 Pg. 1622-1635 (02 22 2018) ISSN: 1520-4804 [Electronic] United States
• PMID: 29400470 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Indoles
• Ophthalmic Solutions
• Protein Kinase Inhibitors
• Pyrazoles
• Pyrimidines
• Vascular Endothelial Growth Factor Receptor-2
• acrizanib

Topics

• Administration, Topical
• Animals
• Choroidal Neovascularization
• Drug Discovery
• Indoles (administration & dosage, pharmacokinetics, therapeutic use)
• Ophthalmic Solutions
• Protein Kinase Inhibitors
• Pyrazoles (administration & dosage, pharmacokinetics, therapeutic use)
• Pyrimidines (administration & dosage, pharmacokinetics, therapeutic use)
• Rabbits
• Rodentia
• Structure-Activity Relationship
• Vascular Endothelial Growth Factor Receptor-2 (antagonists & inhibitors)
• Wet Macular Degeneration (drug therapy)