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| 5mg | ||
| 10mg | ||
| 25mg | ||
| 50mg |
TG 100801 HCl (TG-100801; TG100801), the hydrochloride salt of TG100801, is an ester prodrug of TG-100572 (TG 100572). TG100801 is a novel and potent dual inhibitor of VEGFr2 and the Src family (Src/YES) kinases with the potential to be used for the treatment of AMD (age-related macular degeneration). It can be topically administered, and can inhibit RTK (receptor tyrosine kinases) and Src kinases such as VEGFR1, VEGFR2, FGFR1, FGFR2, PDGFRβ, Fgr, Fyn, Hck, Lck, Lyn, Src, and Yes with IC50s of 2, 7, 2, 16, 13, 5, 0.5, 6, 0.1, 0.4, 1, 0.2 nM, respectively.
| ln Vitro |
As eye drops, TG 100801 is a prodrug that is applied topically and quickly changes into active TG 100572 in the eye. It was demonstrated that TG 100572 inhibited the growth of hRMVEC cells at an IC50 of 610±72 nM[1]. Derivatizing the phenolic moiety in TG100572 to yield an ester yields TG 100801. It demonstrates a superb equilibrium between hydrolysis rate and stability (chemical and physical). Because the ester group prevents important interactions with the kinase active site, TG 100801 by itself does not demonstrate significant antikinase activity. However, exposure to esterases, which are prevalent in mammalian tissues, quickly releases active TG 100572. Subnanomolar action is demonstrated by TG 100572 against the Src family and RTKs, including VEGFR1 and R2, FGFR1 and R2, and PDGFRβ. TG 100572 prevents VEGF-induced extracellular signal-regulated kinase phosphorylation and reduces the proliferation of vascular endothelial cells (ED50=610±71 nM). While quiescent endothelial cell cultures are immune to TG 100572, they are susceptible to apoptosis when endothelial cell cultures proliferate quickly [2].
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| ln Vivo |
In a laser-induced choroidal neovascularization model, TG 100801 demonstrates promising efficacy and demonstrates poor systemic circulation along with excellent ocular pharmacokinetics. The concentration of TG 100572 in the choroid and sclera increases over 30 minutes (Tmax) = 0.5 hours to 23.4 µM (Cmax). TG 100572 levels in the retina are, nevertheless, comparatively low. Because TG 100572 has a brief half-life in ocular tissue, the compound must be applied topically with little time intervals in order to keep the right amount of medication in the eye. In formulations utilizing TG 100572, the highest concentration that can be achieved is 0.7% w/v[1]. TG 100801 or TG100572 was detectable in plasma after topical administration, and even with prolonged dosing regimens, no adverse safety signals (like weight loss) were noted. Topical TG 100801 significantly reduces retinal vein occlusion or fluorescein leakage in the vasculature, as well as laser-induced choroidal neovascularization in mice and rat models. It also thickens the retina. In a laser-induced mouse model, systemic administration of TG 100572 to choroidal neovascularization (CNV) resulted in a significant inhibition of CNV; however, the weight loss that accompanied the CNV development suggested systemic toxicity [2].
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| References |
[1]. Palanki MS, et al. 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. J Med Chem. 2008 Mar 27;51(6):1546-59.
[2]. Doukas, John, et al. Topical administration of a multi-targeted kinase inhibitor suppresses choroidal neovascularization and retinal edema. Journal of Cellular Physiology (2008), 216(1), 29-37 |
| Molecular Formula |
C33H30N5O3CL.HCL
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|---|---|
| Molecular Weight |
616.53694
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| CAS # |
1018069-81-2
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| Related CAS # |
TG 100801;867331-82-6
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| Appearance |
Typically exists as solids (or liquids in special cases) at room temperature
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| SMILES |
O=C(C1=CC=CC=C1)OC2=CC=C(Cl)C(C3=CC(C)=C(N=C(NC(C=C4)=CC=C4OCCN5CCCC5)N=N6)C6=C3)=C2.Cl
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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 mg/mL (~8.11 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 | 1.6220 mL | 8.1098 mL | 16.2195 mL | |
| 5 mM | 0.3244 mL | 1.6220 mL | 3.2439 mL | |
| 10 mM | 0.1622 mL | 0.8110 mL | 1.6220 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.
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