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| | GSK2110183B Basic information |
| Product Name: | GSK2110183B | | Synonyms: | Afuresertib (hydrochloride);GSK 2110183B;GSK2110183B;GSK-2110183B;GSK 2110183 hydrochloride;GSK2110183 hydrochloride;GSK-2110183 hydrochloride;N-((S)-1-Amino-3-(3-fluorophenyl)propan-2-yl)-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)thiophene-2-carboxamide hydrochloride | | CAS: | 1047645-82-8 | | MF: | C18H18Cl3FN4OS | | MW: | 463.78 | | EINECS: | | | Product Categories: | | | Mol File: | 1047645-82-8.mol |  |
| | GSK2110183B Chemical Properties |
| storage temp. | Store at -20°C, protect from light, stored under nitrogen | | solubility | DMSO:65.0(Max Conc. mg/mL);140.15(Max Conc. mM)
DMF:50.0(Max Conc. mg/mL);107.81(Max Conc. mM)
Ethanol:50.0(Max Conc. mg/mL);107.81(Max Conc. mM)
Ethanol:PBS (pH 7.2) (1:1):0.5(Max Conc. mg/mL);1.08(Max Conc. mM) | | form | A crystalline solid | | color | Yellow to brown |
| | GSK2110183B Usage And Synthesis |
| Uses | Afuresertib is a selective, orally bioavailable inhibitor of Akt1, 2, and 3 with Ki values of 0.08, 2, and 2.6 nM, respectively. It preferentially inhibits the proliferation of human cancer cell lines with Akt pathway activation and various cell lines derived from hematologic malignancies with minimal effect on glucose homeostasis. Afuresertib demonstrates activity against multiple myeloma in both preclinical and clinical models.[Cayman Chemical] | | Synthesis | The general procedure for the synthesis of N-((S)-1-amino-3-(3-fluorophenyl)propan-2-yl)-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)thiophene-2-carboxamide as a hydrochloride salt was as follows: 5 mL of methyl tert-butyl ether (MTBE) was added to 213.9 mg (0.500 mmol) of the amorphous free base and the mixture was heated under magnetic The mixture was heated to 40 °C under magnetic stirring and maintained for 1 hour. Subsequently, a 1,4-dioxane solution of 4 M HCl was added in four additions (totaling 1 equiv, 125.1 μL). After the first addition of 0.25 equivalents of HCl solution, the mixture was heated to 42 °C and 1 mL of acetonitrile was added to completely dissolve the solid. After the remaining HCl solution was added, solid precipitation was observed. The slurry was stirred at 42°C for 4 hours, then held sequentially at 35°C, 30°C, and 25°C for 90 minutes each at a rate of 5°C per hour, and finally cooled slowly to 22°C overnight. The white solid was collected by filtration and dried under vacuum at 50 °C while slowly purged by passing nitrogen overnight. The yield of the resulting hydrochloride was 73.6% (0.3685 mmol, 170.90 mg). The product was confirmed to be HCl salt with stoichiometric ratio of 1:1 by ion chromatography analysis, and the powder X-ray diffraction (PXRD) pattern (Figure 1) showed it to be in the crystalline state, with the following characteristic diffraction peaks, and a melting point of 211 °C. The characteristic PXRD peaks (2θ values, with d-spacing in parentheses): 7.2° (12.20 ) , 14.4° (6.16 ) , 17.9° (4.94 ) , 18.5° (4.79 ) , 20.8° (4.26 ) , 21.5° (4.12 ) , 22.4° (3.96 ) , 22.9° (3.88 ) , 23.7° (3.75 ) , 24.5° (3.63 ) , 24.7° (3.61 ) , 25.1° (4.12 ) , 25.7° (3.46 ) , 27.3° (3.26 ) , 28.2° (3.16 ) , 28.8° (3.10 ) , 30.4° (2.94 ) , 32.4° (2.76 ) , 32.7° (2.73 ) , 35.2° (2.55 ) , 36.1° (2.48 ) , 40.0° (2.25 ) , 41.3° (2.18 ) , 41.7° (2.16 ) The Measuring instrument: Panaco X'Pert-Pro MPD diffractometer with Johansson monochromator (Cu Kα1 radiation, wavelength 1.540598 ) and X'Celerator detector. Key test parameters: voltage 45 kV, current 40 mA, start angle 2.0° 2θ, end angle 52.0° 2θ, step size 0.02°, counting time per step 40.0 s, scanning speed 0.05°/sec. Incident beam configuration: 2° fixed anti-scattering slit, programmable divergence slit; diffraction beam configuration: 0.02 rad Soller slit, programmable anti-scattering slit. Samples were prepared on a silicon zero background sample holder. | | in vivo | Mice bearing BT474 breast tumor xenografts are dosed orally with either vehicle or GSK2110183 at 10, 30 or 100 mg/kg daily for 21 days which result in 8, 37 and 61% TGI, respectively. Mice tolerated GSK2110183 well, with 1-3% body weight loss reported after 5 days of dosing which recover over the course of the study. Other tumor xenograft models which possess an activation of the Akt pathway are explored to further demonstrate compound efficacy. Mice treated with GSK2110183 at 10, 30 and 100 mg/kg result in 23, 37 and 97% TGI, respectively, of SKOV3 xenografts[2]. | | IC 50 | Akt1: 0.08 nM (Ki); Akt2: 2 nM (Ki); Akt3: 2.6 nM (Ki); Akt1 E17K mutant: 0.2 nM (IC50); PKCη: 210 nM (IC50); PKC-βI: 430 nM (IC50); ROCK: 100 nM (IC50); PKCθ: 510 nM (IC50) | | References | [1] Patent: US2010/197754, 2010, A1. Location in patent: Page/Page column 8-9
[2] Patent: WO2008/98104, 2008, A1. Location in patent: Page/Page column 191-192 |
| | GSK2110183B Preparation Products And Raw materials |
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