TG 100801 - CAS 867331-82-6
Catalog number: B0084-429718
Category: Inhibitor
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TG 100801 is the prodrug of TG 100572, which is a multi-targeted kinase inhibitor that inhibit select growth factor receptor tyrosine kinases and Src familt kinases. It is currently in a clinical trial as a first in class, VEGFr2 targeting, topically applied compound for the treatment of AMD. It is a new drug that inhibits ocular angiogenesis, vascular leak, and inflammation in laboratory studies.
TG 100801; TG100801; TG-100801
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1.Neovascular age-related macular degeneration: potential therapies.
Chappelow AV;Kaiser PK Drugs. 2008;68(8):1029-36.
Age-related macular degeneration (AMD) affects an estimated 14 million people worldwide, and is the leading cause of severe, irreversible vision loss in individuals over the age of 50 years in Western societies. Choroidal neovascularization (CNV), the hallmark of 'wet', 'exudative' or 'neovascular' AMD, is responsible for approximately 90% of cases of severe vision loss due to AMD. Vascular endothelial growth factor (VEGF) has been shown to play a key role in the regulation of CNV and vascular permeability. Ranibizumab, the current gold standard in the US for the treatment of neovascular AMD, exerts its effect through binding and inhibition of all isoforms of VEGF. Randomized controlled clinical trials have established ranibizumab as the first US FDA-approved therapy for neovascular AMD to result in improvement in visual acuity. Despite impressive outcomes, treatment with ranibizumab requires sustained treatment regimens and frequent intravitreal injections. In this review, we discuss promising emerging therapies for neovascular AMD that aim to improve outcomes, safety and treatment burden through novel mechanisms of action. Currently in phase III clinical trials, VEGF Trap is a receptor decoy that targets VEGF with higher affinity than ranibizumab and other currently available anti-VEGF agents.
2.Topical administration of a multi-targeted kinase inhibitor suppresses choroidal neovascularization and retinal edema.
Doukas J;Mahesh S;Umeda N;Kachi S;Akiyama H;Yokoi K;Cao J;Chen Z;Dellamary L;Tam B;Racanelli-Layton A;Hood J;Martin M;Noronha G;Soll R;Campochiaro PA J Cell Physiol. 2008 Jul;216(1):29-37. doi: 10.1002/jcp.21426.
Age-related macular degeneration, diabetic retinopathy, and retinal vein occlusions are complicated by neovascularization and macular edema. Multi-targeted kinase inhibitors that inhibit select growth factor receptor tyrosine kinases and/or components of their down-stream signaling cascades (such as Src kinases) are rationale treatment strategies for these disease processes. We describe the discovery and characterization of two such agents. TG100572, which inhibits Src kinases and selected receptor tyrosine kinases, induced apoptosis of proliferating endothelial cells in vitro. Systemic delivery of TG100572 in a murine model of laser-induced choroidal neovascularization (CNV) caused significant suppression of CNV, but with an associated weight loss suggestive of systemic toxicity. To minimize systemic exposure, topical delivery of TG100572 to the cornea was explored, and while substantial levels of TG100572 were achieved in the retina and choroid, superior exposure levels were achieved using TG100801, an inactive prodrug that generates TG100572 by de-esterification. Neither TG100801 nor TG100572 were detectable in plasma following topical delivery of TG100801, and adverse safety signals (such as weight loss) were not observed even with prolonged dosing schedules.
3.Development of prodrug 4-chloro-3-(5-methyl-3-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}-1,2,4-benzotriazin-7-yl)phenyl benzoate (TG100801): a topically administered therapeutic candidate in clinical trials for the treatment of age-related macular degeneration.
Palanki MS;Akiyama H;Campochiaro P;Cao J;Chow CP;Dellamary L;Doukas J;Fine R;Gritzen C;Hood JD;Hu S;Kachi S;Kang X;Klebansky B;Kousba A;Lohse D;Mak CC;Martin M;McPherson A;Pathak VP;Renick J;Soll R;Umeda N;Yee S;Yokoi K;Zeng B;Zhu H;Noronha G J Med Chem. 2008 Mar 27;51(6):1546-59. doi: 10.1021/jm7011276. Epub 2008 Feb 27.
Age-related macular degeneration (AMD) is one of the leading causes of loss of vision in the industrialized world. Attenuating the VEGF signal in the eye to treat AMD has been validated clinically. A large body of evidence suggests that inhibitors targeting the VEGFr pathway may be effective for the treatment of AMD. Recent studies using Src/YES knockout mice suggest that along with VEGF, Src and YES play a crucial role in vascular leak and might be useful in treating edema associated with AMD. Therefore, we have developed several potent benzotriazine inhibitors designed to target VEGFr2, Src, and YES. One of the most potent compounds is 4-chloro-3-{5-methyl-3-[4-(2-pyrrolidin-1-yl-ethoxy)phenylamino]benzo[1,2,4]triazin-7-yl}phenol ( 5), a dual inhibitor of both VEGFr2 and the Src family (Src and YES) kinases. Several ester analogues of 5 were prepared as prodrugs to improve the concentration of 5 at the back of the eye after topical administration. The thermal stability of these esters was studied, and it was found that benzoyl and substituted benzoyl esters of 5 showed good thermal stability. The hydrolysis rates of these prodrugs were studied to analyze their ability to undergo conversion to 5 in vivo so that appropriate concentrations of 5 are available in the back-of-the-eye tissues.
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CAS 867331-82-6 TG 100801

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