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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.
J Med Chem 2018; 61(4):1622-1635JM

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+Show Affiliations

Global Discovery Chemistry, Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.Ophthalmology, Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.Global Discovery Chemistry, Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.Pharmacokinetic Sciences, Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue, Cambridge Massachusetts 02139, United States.Ophthalmology, Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.Global Discovery Chemistry, Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.Ophthalmology, Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.Global Drug Development/Technical Research & Development, Novartis Pharmaceutical Corporation , 6201 South Freeway Fort Worth, Texas 76134-2099, United States.Ophthalmology, Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.Global Discovery Chemistry, Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.Pharmacokinetic Sciences, Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue, Cambridge Massachusetts 02139, United States.Ophthalmology, Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.Global Discovery Chemistry, Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.Global Discovery Chemistry, Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.Global Discovery Chemistry, Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.Pharmacokinetic Sciences, Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue, Cambridge Massachusetts 02139, United States.Global Discovery Chemistry, Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.Ophthalmology, Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.Ophthalmology, Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.Global Discovery Chemistry, Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.Global Discovery Chemistry, Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.Global Discovery Chemistry, Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.Global Discovery Chemistry, Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.Ocular Pharmacokinetics and Disposition, Alcon, a Novartis Company , 201 South Freeway, Fort Worth, Texas 76134, United States.Ophthalmology, Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.Global Discovery Chemistry, Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.Ophthalmology, Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.Global Discovery Chemistry, Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.Ophthalmology, Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.Ophthalmology, Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.Global Discovery Chemistry, Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.Chemical and Pharmaceutical Profiling, Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.Ophthalmology, Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.Global Discovery Chemistry, Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.Ophthalmology, Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29400470

Citation

Adams, Christopher M., et al. "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, vol. 61, no. 4, 2018, pp. 1622-1635.
Adams CM, Anderson K, Artman G, et al. 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;61(4):1622-1635.
Adams, C. M., Anderson, K., Artman, G., Bizec, J. C., Cepeda, R., Elliott, J., ... Zhang, Y. (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, 61(4), pp. 1622-1635. doi:10.1021/acs.jmedchem.7b01731.
Adams CM, et al. 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 02 22;61(4):1622-1635. PubMed PMID: 29400470.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Adams,Christopher M, AU - Anderson,Karen, AU - Artman,Gerald,3rd AU - Bizec,Jean-Claude, AU - Cepeda,Rosemarie, AU - Elliott,Jason, AU - Fassbender,Elizabeth, AU - Ghosh,Malay, AU - Hanks,Shawn, AU - Hardegger,Leo A, AU - Hosagrahara,Vinayak P, AU - Jaffee,Bruce, AU - Jendza,Keith, AU - Ji,Nan, AU - Johnson,Leland, AU - Lee,Wendy, AU - Liu,Donglei, AU - Liu,Fang, AU - Long,Debby, AU - Ma,Fupeng, AU - Mainolfi,Nello, AU - Meredith,Erik L, AU - Miranda,Karl, AU - Peng,Yao, AU - Poor,Stephen, AU - Powers,James, AU - Qiu,Yubin, AU - Rao,Chang, AU - Shen,Siyuan, AU - Sivak,Jeremy M, AU - Solovay,Catherine, AU - Tarsa,Peter, AU - Woolfenden,Amber, AU - Zhang,Chun, AU - Zhang,Yiqin, Y1 - 2018/02/05/ PY - 2018/2/6/pubmed PY - 2019/4/16/medline PY - 2018/2/6/entrez SP - 1622 EP - 1635 JF - Journal of medicinal chemistry JO - J. Med. Chem. VL - 61 IS - 4 N2 - 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. SN - 1520-4804 UR - https://www.unboundmedicine.com/medline/citation/29400470/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_ L2 - https://dx.doi.org/10.1021/acs.jmedchem.7b01731 DB - PRIME DP - Unbound Medicine ER -