| Size | Price | Stock | Qty |
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| 5mg |
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| 10mg |
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| 25mg |
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| 50mg |
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| Other Sizes |
Purity: ≥98%
| Targets |
VEGFR1 (IC50 = 2 nM); VEGFR2 (IC50 = 7 nM); FGFR1 (IC50 = 2 nM); FGFR2 (IC50 = 16 nM); PDGFRβ (IC50 = 13 nM)
TG 100801 is a prodrug of TG 100572, which is a multi-targeted kinase inhibitor. The active metabolite TG 100572 inhibits receptor tyrosine kinases (RTKs) and Src kinases. The targets of TG 100572 include VEGFR1, VEGFR2, FGFR1, FGFR2, PDGFRβ, and the Src family kinases Fgr, Fyn, Hck, Lck, Lyn, Src, and Yes. The IC50 values for these targets range from 0.1 to 16 nM. |
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| ln Vitro |
TG 100801, a prodrug applied topically and administered as an eye drop, is easily changed in the eye to become the active TG 100572.It has been demonstrated that TG 100572 inhibits the proliferation of hRMVEC cells, with an IC50 of 610±72 nM[1]. An ester is produced by derivitization of a phenolic moiety in TG100572 to form TG 100801. It exhibits a superb equilibrium between the rate of hydrolysis and stability (chemical and physical). While the ester group in TG 100801 prevents important interactions with kinase active sites, it lacks significant anti-kinase activity when used alone. However, TG 100801 becomes active very quickly when exposed to esterases, which are prevalent in mammalian tissues. TG 100572 exhibits sub-nanomolar activity against RTK and members of the Src family, including VEGFR1 and R2, FGFR1 and R2, and PDGFRβ. TG 100572 inhibits the proliferation of vascular endothelial cells (ED50=610±71 nM) and prevents extracellular signal-regulated kinase from being phosphorylated by VEGF. In cultures of endothelial cells that are rapidly proliferating but not quiescent, TG 100572 induces apoptosis[2].
TG 100801 is a prodrug that is de-esterified to generate the active multi-targeted kinase inhibitor TG 100572. TG 100572 shows sub-nanomolar activity against the Src family kinases as well as RTKs such as VEGFR1, VEGFR2, FGFR1, FGFR2, and PDGFRβ. TG 100572 inhibits vascular endothelial cell proliferation with an ED50 of 610±71 nM and blocks VEGF-induced phosphorylation of extracellular signal-regulated kinase. It induces apoptosis in rapidly proliferating, but not quiescent, endothelial cell cultures. TG 100572 inhibits hRMVEC cell proliferation with an IC50 of 610±72 nM. |
| ln Vivo |
TG 100801 demonstrates good efficacy in the laser-induced choroidal neovascularization model, with poor systemic circulation and excellent ocular pharmacokinetics. In 30 min (Tmax) = 0.5 h, TG 100572 reaches a concentration of 23.4 µM (Cmax) in the choroid and sclera. TG 100572 levels in the retina, however, are comparatively low. TG 100572 has a very short half-life in ocular tissues, so in order to maintain proper drug levels in the eye, the compound is applied topically at least once every day. In formulations utilizing TG 100572, the highest concentration that can be attained is 0.7% w/v[1]. After TG 100801 is applied topically, neither TG 100801 nor TG 100572 are detectable in plasma, and even with extended dosing regimens, negative safety signals (like weight loss) are not seen. Topical TG 100801 suppresses retinal vein occlusion and fluorescein leakage from the vasculature, as well as laser-induced choroidal neovascularlization in mice. It also reduces retinal thickening as determined by optical coherence tomography in a rat model. When TG 100572 is administered systemically to mice in a model of laser-induced choroidal neovascularization (CNV), the condition is significantly suppressed, but there is also a weight loss that may indicate systemic toxicity[2].
TG 100801 is administered topically as an eye drop and is readily converted to the active TG 100572 in the eye. The compound is designed for topical ocular delivery to reduce abnormal blood vessel growth and vascular leakage in the retina. In a murine model of laser-induced choroidal neovascularization (CNV), systemic delivery of TG 100572 causes significant suppression of CNV. After topical administration, a concentration of 23.4 μM (Cmax) of TG 100572 is reached in 30 min (Tmax=0.5 h) in the choroid and sclera, with relatively low levels in the retina. |
| Enzyme Assay |
The in vitro kinase inhibition assay for TG 100572 involves incubating the compound with various recombinant kinases (VEGFR1, VEGFR2, FGFR1, FGFR2, PDGFRβ, Src family kinases) in the presence of ATP and a peptide substrate. The reaction is initiated by adding the kinase and terminated by adding a stop solution containing EDTA. The amount of phosphorylated substrate is quantified using a kinase activity assay kit, such as a homogeneous time-resolved fluorescence (HTRF) or luminescence-based assay. IC50 values are calculated from dose-response curves. TG 100572 itself is used in these assays, as TG 100801 is the prodrug.
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| Cell Assay |
The effect of TG 100572 on endothelial cell proliferation is assessed using human retinal microvascular endothelial cells (hRMVECs). Cells are seeded in 96-well plates and treated with varying concentrations of TG 100572 (e.g., 0.1 nM to 10 μM) in the presence of VEGF. After 72 hours of incubation, cell proliferation is measured using a colorimetric assay, such as MTS or WST-1. The IC50 for inhibition of cell proliferation is calculated. Apoptosis is assessed by staining cells with annexin V-FITC and propidium iodide, followed by flow cytometry analysis.
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| Animal Protocol |
Rats: Either 10 µL of TG 100801 (in the form of a 0.3, 0.6, or 1% solution) or vehicle is applied topically to both eyes of long Evans rats. Over a three-day period, each eye receives a total of five topical applications: dosing is done twice on Day 2 and once in the morning of Day 3, one hour before and six hours after laser-induced thrombosis. There are two methods for assessing retinal edema an hour after the last topical application[2].
The in vivo efficacy of TG 100801 is evaluated in a murine model of laser-induced choroidal neovascularization (CNV). C57BL/6 mice are subjected to laser photocoagulation to induce CNV. TG 100801 is administered topically as eye drops (e.g., at a concentration of 0.7% w/v) multiple times daily (t.i.d.). After a treatment period (e.g., 7-14 days), the area of CNV is measured in choroidal flat mounts using fluorescent staining (e.g., FITC-dextran). The extent of suppression of CNV is expressed as the percentage reduction in CNV area compared to vehicle-treated controls. |
| ADME/Pharmacokinetics |
The active metabolite TG 100572 has a very short half-life in ocular tissues, necessitating topical administration at least three times daily (t.i.d.) to maintain appropriate drug levels in the eye. The maximum concentration that can be achieved in formulations using TG 100572 is 0.7% w/v. In a murine model, systemic delivery of TG 100572 was associated with weight loss, suggestive of systemic toxicity. The prodrug approach of TG 100801 is designed to deliver the active compound locally to the eye while minimizing systemic exposure.
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| Toxicity/Toxicokinetics |
In a murine model of laser-induced CNV, systemic delivery of TG 100572 causes significant suppression of CNV but is associated with weight loss suggestive of systemic toxicity. This supports the development of TG 100801 as a topical prodrug to improve the therapeutic index by delivering the active agent locally to the eye. TG 100801 is intended for the treatment of AMD and offers a non-invasive alternative to intravitreal injections.
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| References |
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| Additional Infomation |
TG100801 is a topical kinase inhibitor for the treatment of macular degeneration. It is administered noninvasively as eye drops and is designed to inhibit VEGF-mediated leakage and other kinase targets associated with inflammation, edema, and angiogenesis—pathological hallmarks of age-related macular degeneration (AMD) and other posterior ocular diseases, including diabetic macular edema and proliferative diabetic retinopathy.
Drug Indications Investigations are underway for the treatment of macular degeneration. Mechanism of Action TG100801 is the first topical, multi-target vascular endothelial growth factor receptor (VEGFR)/Src kinase inhibitor to enter clinical trials. In relevant preclinical models of macular degeneration, TG100801 significantly reduced VEGF-mediated retinal leakage and choroidal neovascularization. In cell-based experiments, after topical eye drops, TG100572 (an active drug derived from TG100801 that has penetrated into the eye) was shown to induce apoptosis in proliferative endothelial cells responsible for angiogenesis and to inhibit inflammation-mediated processes (measured by endotoxin-induced nitric oxide release in vitro). TG 100801 is a prodrug that is de-esterified to generate the active multi-targeted kinase inhibitor TG 100572. It has a molecular weight of 580.08 g/mol and a formula of C33H30ClN5O3. The compound is used in research on age-related macular degeneration (AMD). TG 100801 is designed for topical ocular delivery. It is supplied for laboratory research only and is documented in chemical databases. |
| Molecular Formula |
C33H30CLN5O3
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|---|---|
| Molecular Weight |
580.076
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| Exact Mass |
579.203
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| Elemental Analysis |
C, 68.33; H, 5.21; Cl, 6.11; N, 12.07; O, 8.27
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| CAS # |
867331-82-6
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| Related CAS # |
TG 100801 Hydrochloride;1018069-81-2
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| PubChem CID |
11973736
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| Appearance |
Brown to reddish brown solid powder
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
747.9±70.0 °C at 760 mmHg
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| Flash Point |
406.1±35.7 °C
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| Vapour Pressure |
0.0±2.5 mmHg at 25°C
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| Index of Refraction |
1.669
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| LogP |
6.64
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
10
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| Heavy Atom Count |
42
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| Complexity |
848
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C(C1C=CC=CC=1)OC1C=C(C2C=C(C)C3C(=NN=C(NC4C=CC(OCCN5CCCC5)=CC=4)N=3)C=2)C(Cl)=CC=1
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| InChi Key |
JMGXJHWTVBGOKG-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C33H30ClN5O3/c1-22-19-24(28-21-27(13-14-29(28)34)42-32(40)23-7-3-2-4-8-23)20-30-31(22)36-33(38-37-30)35-25-9-11-26(12-10-25)41-18-17-39-15-5-6-16-39/h2-4,7-14,19-21H,5-6,15-18H2,1H3,(H,35,36,38)
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| Chemical Name |
[4-chloro-3-[5-methyl-3-[4-(2-pyrrolidin-1-ylethoxy)anilino]-1,2,4-benzotriazin-7-yl]phenyl] benzoate
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| Synonyms |
TG100801; TG-100801; TG 100801
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO: ~5.6 mg/mL (~9.6 mM)
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.7239 mL | 8.6195 mL | 17.2390 mL | |
| 5 mM | 0.3448 mL | 1.7239 mL | 3.4478 mL | |
| 10 mM | 0.1724 mL | 0.8620 mL | 1.7239 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT00414999 | Completed | Drug: TG100801 | Macular Degeneration Diabetic Retinopathy |
TargeGen | November 2006 | Phase 1 |
| NCT00509548 | Terminated | Drug: TG100801 | Macular Degeneration Choroidal Neovascularization |
TargeGen | July 2007 | Phase 2 |
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