title: Discovery of Oral VEGFR-2 Inhibitors with Prolonged Ocular Retention That Are Efficacious in Models of Wet Age-Related Macular Degeneration.
abstract: The benefit of intravitreal anti-VEGF therapy in treating wet age-related macular degeneration (AMD) is well established. Identification of VEGFR-2 inhibitors with optimal ADME properties for an ocular indication provides opportunities for dosing routes beyond intravitreal injection. We employed a high-throughput in vivo screening strategy with rodent models of choroidal neovascularization and iterative compound design to identify VEGFR-2 inhibitors with potential to benefit wet AMD patients. These compounds demonstrate preferential ocular tissue distribution and efficacy after oral administration while minimizing systemic exposure.
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for BioMedical Research , 100 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Erik L
authors.initials: EL
authors.lastname: Meredith
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for BioMedical Research , 100 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Nello
authors.initials: N
authors.lastname: Mainolfi
authors.affiliation: Ophthalmology, Novartis Institutes for BioMedical Research , 500 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Stephen
authors.initials: S
authors.lastname: Poor
authors.affiliation: Ophthalmology, Novartis Institutes for BioMedical Research , 500 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Yubin
authors.initials: Y
authors.lastname: Qiu
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for BioMedical Research , 100 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Karl
authors.initials: K
authors.lastname: Miranda
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for BioMedical Research , 100 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: James
authors.initials: J
authors.lastname: Powers
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for BioMedical Research , 100 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Donglei
authors.initials: D
authors.lastname: Liu
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for BioMedical Research , 100 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Fupeng
authors.initials: F
authors.lastname: Ma
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for BioMedical Research , 100 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Catherine
authors.initials: C
authors.lastname: Solovay
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for BioMedical Research , 100 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Chang
authors.initials: C
authors.lastname: Rao
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for BioMedical Research , 100 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Leland
authors.initials: L
authors.lastname: Johnson
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for BioMedical Research , 100 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Nan
authors.initials: N
authors.lastname: Ji
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for BioMedical Research , 100 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Gerald
authors.initials: G
authors.lastname: Artman
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for BioMedical Research , 100 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Leo
authors.initials: L
authors.lastname: Hardegger
authors.affiliation: Ophthalmology, Novartis Institutes for BioMedical Research , 500 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Shawn
authors.initials: S
authors.lastname: Hanks
authors.affiliation: Ophthalmology, Novartis Institutes for BioMedical Research , 500 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Siyuan
authors.initials: S
authors.lastname: Shen
authors.affiliation: Ophthalmology, Novartis Institutes for BioMedical Research , 500 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Amber
authors.initials: A
authors.lastname: Woolfenden
authors.affiliation: Ophthalmology, Novartis Institutes for BioMedical Research , 500 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Fassbender
authors.affiliation: Ophthalmology, Novartis Institutes for BioMedical Research , 500 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Sivak
authors.affiliation: Ophthalmology, Novartis Institutes for BioMedical Research , 500 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Yiqin
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Ophthalmology, Novartis Institutes for BioMedical Research , 500 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Debby
authors.initials: D
authors.lastname: Long
authors.affiliation: Ophthalmology, Novartis Institutes for BioMedical Research , 500 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Rosemarie
authors.initials: R
authors.lastname: Cepeda
authors.affiliation: Ophthalmology, Novartis Institutes for BioMedical Research , 500 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
authors.affiliation: Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue, Cambridge Massachusetts 02139, United States.
authors.forename: Vinayak P
authors.initials: VP
authors.lastname: Hosagrahara
authors.affiliation: Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue, Cambridge Massachusetts 02139, United States.
authors.forename: Wendy
authors.initials: W
authors.lastname: Lee
authors.affiliation: Chemical and Pharmaceutical Profiling, Novartis Institutes for BioMedical Research , 500 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Peter
authors.initials: P
authors.lastname: Tarsa
authors.affiliation: Ophthalmology, Novartis Institutes for BioMedical Research , 500 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Karen
authors.initials: K
authors.lastname: Anderson
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for BioMedical Research , 100 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Jason
authors.initials: J
authors.lastname: Elliott
authors.affiliation: Ophthalmology, Novartis Institutes for BioMedical Research , 500 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Bruce
authors.initials: B
authors.lastname: Jaffee
mesh_terms: D000284:Administration, Oral; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000818:Animals; D002829:Choroid / Q000187:drug effects / Q000473:pathology; D020256:Choroidal Neovascularization / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D006801:Humans; D058449:Intravitreal Injections; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011743:Pyrimidines / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D051381:Rats; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*; D057135:Wet Macular Degeneration / Q000188:drug therapy* / Q000473:pathology
chemical_list: D020533:Angiogenesis Inhibitors; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D040301:Vascular Endothelial Growth Factor Receptor-2