The Discovery of N-(1-Methy1-5-(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

被引：34

作者：

Adams, Christopher M. ^{[1
]}

Anderson, Karen ^{[2
]}

Artman, Gerald, III ^{[1
,12
]}

Bizec, Jean-Claude ^{[4
,17
]}

Cepeda, Rosemarie ^{[2
]}

Elliott, Jason ^{[1
]}

Fassbender, Elizabeth ^{[2
,16
]}

Ghosh, Malay ^{[6
]}

Hanks, Shawn ^{[2
]}

Hardegger, Leo A. ^{[1
,13
]}

Hosagrahara, Vinayak P. ^{[4
,14
]}

Jaffee, Bruce ^{[2
]}

Jendza, Keith ^{[1
]}

Ji, Nan ^{[1
,7
]}

Johnson, Leland ^{[1
,11
]}

Lee, Wendy ^{[4
]}

Liu, Donglei ^{[1
]}

Liu, Fang

Long, Debby ^{[2
]}

Ma, Fupeng ^{[1
]}

Mainolfi, Nello ^{[1
,7
]}

Meredith, Erik L. ^{[1
]}

Miranda, Karl ^{[1
,10
]}

Peng, Yao ^{[3
,18
]}

Poor, Stephen ^{[2
]}

Powers, James ^{[1
]}

Qu, Yubin ^{[2
]}

Rao, Chang ^{[1
,15
]}

Shen, Siyuan ^{[2
]}

Sivak, Jeremy M. ^{[2
,8
,9
]}

Solovay, Catherine ^{[1
]}

Tarsa, Peter ^{[5
]}

Woolfenden, Amber ^{[2
]}

Zhang, Chun ^{[1
]}

Zhang, Yiqin ^{[2
]}

机构：

[1] Novartis Inst BioMed Res, Global Discovery Chem, 250 Massachusetts Ave, Cambridge, MA 02139 USA

[2] Novartis Inst BioMed Res, Ophthalmol, 250 Massachusetts Ave, Cambridge, MA 02139 USA

[3] Alcon Novartis Co, Ocular Pharmacokinet & Disposit, 201 South Freeway, Ft Worth, TX 76134 USA

[4] Novartis Inst BioMed Res, Pharmacokinet Sci, 250 Massachusetts Ave, Cambridge, MA 02139 USA

[5] Novartis Inst BioMed Res, Chem & Pharmaceut Profiling, 250 Massachusetts Ave, Cambridge, MA 02139 USA

[6] Novartis Pharmaceut, Global Drug Dev Tech Res & Dev, 6201 South Freeway, Ft Worth, TX 76134 USA

[7] Kymera Therapeut LLC, 400 Technol Sq, Cambridge, MA 02139 USA

[8] Univ Toronto, Sch Med, Dept Ophthalmol & Vis Sci, 60 Leonard Ave, Toronto, ON M5T 2S8, Canada

[9] Krembil Res Inst, Div Vis Sci, 60 Leonard Ave, Toronto, ON M5T 2S8, Canada

[10] MyHth Ctr, 45 Sheppard Ave East,Suite 301, Toronto, ON M2N 5W9, Canada

[11] WuXi AppTec55 Cambridge Pkwy, Cambridge, MA 02142 USA

[12] Celgene Corp, 86 Morris Ave, Summit, NJ 07901 USA

[13] Novartis Pharmaceut Chem & Analyt Dev, CH-4002 Basel, Switzerland

[14] EMD Serono Res & Dev Inst Inc, 45A Middlesex Turnpike, Billerica, MA 01821 USA

[15] Nanyang Technol Univ, Sch Biol Sci, 60 Nanyang Dr, Singapore 637551, Singapore

[16] Vertex Pharmaceut, 50 Northern Ave, Boston, MA 02210 USA

[17] 12 Rue Petit Landau, F-68440 Habsheim, France

[18] Covance Labs Inc, 3402 Kinsman Blvd, Madison, WI 53704 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2018年 / 61卷 / 04期

关键词：

ENDOTHELIAL GROWTH-FACTOR; DRUG-DELIVERY; CHOROIDAL NEOVASCULARIZATION; RANIBIZUMAB; MODEL; ANGIOGENESIS; AFLIBERCEPT; EYE;

D O I：

10.1021/acs.jmedchem.7b01731

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 SAP. 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.

引用

页码：1622 / 1635

页数：14

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