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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

Adams, Christopher and Anderson, Karen and Artman Iii, Gerald and Cepeda, Rosemarie and Bizec, Jean-Claude and Elliott, Jason and Fassbender, Elizabeth and Ghosh, Malay and Hanks, Shawn and Hardegger, Leo and Hosagrahara, Vinayak and Jaffee, Bruce and Jendza, Keith and Ji, Nan and Johnson, Leland and Liu, Donglei and Liu, Fang and Long, Debby and Ma, Fupeng and Mainolfi, Nello and Meredith, Erik and Miranda, Karl and Peng, Penny and Poor, Stephen and Powers, James and Qiu, Yubin and Rao, Chang and Shen, Siyuan and Sivak, Jeremy and Solovay, Catherine and Tarsa, Peter and Woolfenden, Amber and Zhang, Chun and Zhang, Yiqin (2018) 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. Journal of Medicinal Chemistry. ISSN 0022-26231520-4804

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 smallmolecule
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.

Item Type: Article
Keywords: AMD, VEGFR-2, topical ocular
Date Deposited: 17 Feb 2018 00:45
Last Modified: 17 Feb 2018 00:45
URI: https://oak.novartis.com/id/eprint/34366

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