2. Academic Validation
  3. 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

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

  • J Med Chem. 2018 Feb 22;61(4):1622-1635. doi: 10.1021/acs.jmedchem.7b01731.
Christopher M Adams 1,  Karen Anderson 2,  Gerald Artman 3rd 1,  Jean-Claude Bizec 3,  Rosemarie Cepeda 2,  Jason Elliott 1,  Elizabeth Fassbender 2,  Malay Ghosh 4,  Shawn Hanks 2,  Leo A Hardegger 1,  Vinayak P Hosagrahara 3,  Bruce Jaffee 2,  Keith Jendza 1,  Nan Ji 1,  Leland Johnson 1,  Wendy Lee 3,  Donglei Liu 1,  Fang Liu 2,  Debby Long 2,  Fupeng Ma 1,  Nello Mainolfi 1,  Erik L Meredith 1,  Karl Miranda 1,  Yao Peng 5,  Stephen Poor 2,  James Powers 1,  Yubin Qiu 2,  Chang Rao 1,  Siyuan Shen 2,  Jeremy M Sivak 2,  Catherine Solovay 1,  Peter Tarsa 6,  Amber Woolfenden 2,  Chun Zhang 1,  Yiqin Zhang 2
Affiliations

Affiliations

  • 1 Global Discovery Chemistry, Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
  • 2 Ophthalmology, Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
  • 3 Pharmacokinetic Sciences, Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue, Cambridge Massachusetts 02139, United States.
  • 4 Global Drug Development/Technical Research & Development, Novartis Pharmaceutical Corporation , 6201 South Freeway Fort Worth, Texas 76134-2099, United States.
  • 5 Ocular Pharmacokinetics and Disposition, Alcon, a Novartis Company , 201 South Freeway, Fort Worth, Texas 76134, United States.
  • 6 Chemical and Pharmaceutical Profiling, Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
PMID: 29400470 DOI: 10.1021/acs.jmedchem.7b01731
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-109020
    99.84%, VEGFR2 抑制剂
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