TG-100801-Hydrochloride - VEGFR 抑制剂 - 生命科学试剂 - MedChemExpress

1、Hotline: 400-820-3792Inhibitors Agonists Screening Librarieswww.MedChemETG 100801 HydrochlorideCat. No.: HY-10187CAS No.: 1018069-81-2分式: CHClNO分量: 616.54作靶点: VEGFR; FGFR; PDGFR; Src作通路: Protein Tyrosine Kinase/RTK储存式: Please store the product under the recommended conditions inthe COA.溶解性数据体外实验 DMS

2、O : 5 mg/mL (8.11 mM; Need ultrasonic)Mass Solvent1 mg 5 mg 10 mg Concentration制备储备液1 mM 1.6220 mL 8.1098 mL 16.2195 mL5 mM 0.3244 mL 1.6220 mL 3.2439 mL10 mM - - -请根据产品在不同溶剂中的溶解度，选择合适的溶剂配制储备液，并请注意储备液的保存式和期限。BIOLOGICAL ACTIVITY物活性 TG 100801 HydrochlorideTG 100572的前药，通过去酯化产TG 100572，开发来治疗年龄相关的黄斑变性。TG

3、 100572是多靶点激酶抑制剂，抑制受体酪氨酸激酶 (receptor tyrosine kinases) 和Src激酶 (Srckinases); 对VEGFR1，VEGFR2，FGFR1，FGFR2，PDGFR，Fgr，Fyn，Hck，Lck，Lyn，Src，Yes 的 IC50值分别为2，7，2，16，13，5，0.5，6，0.1，0.4，1，0.2。IC50 & Target VEGFR1 VEGFR2 FGFR1 FGFR22 nM (IC50) 7 nM (IC50) 2 nM (IC50) 16 nM (IC50)PDGFR1/3 Master of Small Molecul

4、es 您边的抑制剂师www.MedChemE13 nM (IC50)体外研究 TG 100801 is a topically administered prodrug delivered as an eye drop that is readily converted to the activeTG 100572 in the eye.TG 100572 is shown to inhibit hRMVEC cell proliferation, with an IC50 of 61072 nM1. TG 100801 is formed by derivitization of a phe

5、nolic moiety in TG100572 to yield an ester. It displaysexcellent balance of stability (physical and chemical) with hydrolysis rate. On its own, TG 100801 does notdisplay meaningful anti-kinase activity, as the ester group blocks key interactions with kinase active sites,however exposure to esterases

6、 (abundant in mammalian tissues) rapidly liberates active TG100572.TG100572 shows sub-nanomolar activity against the Src family as well as RTK such as VEGFR1 and R2,FGFR1 and R2, and PDGFR. TG 100572 inhibits vascular endothelial cell proliferation (ED50=61071 nM)and blocks VEGF-induced phosphorylat

7、ion of extracellular signal-regulated kinase. TG 100572 inducesapoptosis in rapidly proliferating, but not quiescent, endothelial cell cultures 2.体内研究 TG 100801 exhibits excellent ocular pharmacokinetics and poor systemic circulation and shows goodefficacy in the laser induced choroidal neovasculari

8、zation model. A concentration of 23.4 M (Cmax) of TG100572 is reached in 30 min (Tmax)=0.5 h) in the choroid and the sclera. However, the levels of TG 100572in the retina are relatively low. The half-life of TG 100572 in ocular tissues is very short; hence, thecompound is administered topically mini

9、mum t.i.d. to maintain appropriate drug levels in the eye. Themaximum concentration one can achieve in formulations using TG 100572 is 0.7% w/v 1. TG 100801 norTG100572 are detectable in plasma following topical delivery of TG 100801, and adverse safety signals(such as weight loss) are not observed

10、even with prolonged dosing schedules. Topical TG 100801significantly suppresses laser-induced choroidal neovascularlization in mice, and reduces fluoresceinleakage from the vasculature and retinal thickening measured by optical coherence tomography in a ratmodel or retinal vein occlusion.Systemic de

11、livery of TG 100572 in a murine model of laser-induced choroidalneovascularization (CNV) causes significant suppression of CNV, but with an associated weight losssuggestive of systemic toxicity 2.PROTOCOLAnimal Rats: Long Evans rats are dosed topically in both eyes with 10 L of TG 100801 (as a 0.3,

12、0.6 or 1%Administration 2 solution) or vehicle. A total of 5 topical applications are delivered per eye over a three day period: dosing isperformed one hour prior to and six hours after laser-induced thrombosis on Day 1, twice on Day 2, and oncethe morning of Day 3. One hour after the final topical

13、application, retinal edema is assessed by one of twomeans 2.MCE has not independently confirmed the accuracy of these methods. They are for reference only.户使本产品发表的科研献 Science. 2017 Dec 1;358(6367).See more customer validations on HYPERLINK / www.MedChemEREFERENCES2/3 Master of Small Molecules 您边的抑制剂

14、师www.MedChemE1. Palanki MS, et al. Development of prodrug 4-chloro-3-(5-methyl-3-4-(2-pyrrolidin-1-ylethoxy)phenylamino-1,2,4-benzotriazin-7-yl)phenyl benzoate (TG100801): a topically administered therapeutic candidate in clinical trials for the treatment of age-related maculardegeneration. 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 retinaledema. Journal of Cellular Physiology (20