| Identification | Back Directory | [Name]
Decernotinib | [CAS]
944842-54-0 | [Synonyms]
VX 509
CS-1650
VRT 831509
adelatinib
Decernotinib
VX-509;VRT-831509
Decernotinib(VX-509)
VX-509;? VRT-831509; ADELATINIB
Decernotinib (VX-509,adelatinib)
(R)-2-((2-(1H-Pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamide
(2R)-2-Methyl-2-[[2-(1H-pyrrolo[2,3-b]pyridin-3-yl)-4-pyrimidinyl]amino]-N-(2,2,2-trifluoroethyl)butanamide
Butanamide, 2-methyl-2-[[2-(1H-pyrrolo[2,3-b]pyridin-3-yl)-4-pyrimidinyl]amino]-N-(2,2,2-trifluoroethyl)-, (2R)- | [Molecular Formula]
C18H19F3N6O | [MDL Number]
MFCD27987896 | [MOL File]
944842-54-0.mol | [Molecular Weight]
392.38 |
| Chemical Properties | Back Directory | [density ]
1.363±0.06 g/cm3(Predicted) | [storage temp. ]
4°C, protect from light, stored under nitrogen | [solubility ]
insoluble in H2O; ≥16.95 mg/mL in DMSO; ≥2.92 mg/mL in EtOH with ultrasonic | [form ]
solid | [pka]
12.36±0.40(Predicted) | [color ]
White to off-white | [InChIKey]
ASUGUQWIHMTFJL-QGZVFWFLSA-N | [SMILES]
C(NCC(F)(F)F)(=O)[C@](C)(NC1C=CN=C(C2C3=CC=CN=C3NC=2)N=1)CC |
| Hazard Information | Back Directory | [Uses]
Decernotinib is a potent and selective Janus kinase 3 inhibitor for treatment of autoimmune diseases. | [Biological Activity]
decernotinib(vx-509)is a novel, potent and selective inhibitor of jak3 with ki value of 2 nm [1].the janus kinase family consists of four members: jak1, jak2, jak3, and tyk2. janus kinase 3 (jak3) is mainly expressed in lymphocytes, which are cells important to the immune response associated with many diseases, including rheumatoid arthritis (ra) [1].decernotinib(vx-509)is a novel, potent, selective and orally available jak3 inhibitor for the treatment of autoimmune diseases. vx-509 inhibited jak1, jak2, jak3, and tyk2 with ki values of 11, 13, 2 and 11 nm, respectively. in ht-2 or tf-1 cells, vx-509 inhibited jak3/1- or jak2-mediated phosphorylation of stat5 following stimulation with il-2 or gmcsf with ic50 values of 99 and 2600 nm, respectively [1].in the rat host versus graft (hvg) model, vx-509 at 50 mg/kg bid or 100 mg/kg qd significantly and dose-dependently inhibited popletial lymph node (pln) hyperplasia by 66% and 94%, respectively, relative to cyclosporin a (csa). vx-509 also significantly reduced cd25 expression. these results suggested that vx-509 showed significant dose-dependent immunosuppressive activity and effectively inhibited t-cell activation [1]. in the rat collagen-induced arthritis model, vx-509 dose-dependently reduced ankle swelling and paw weight, and improved paw histopathology scores. in oxazolone-induced delayed-type hypersensitivity mouse model, vx-509 reduced the t cell-mediated inflammatory response in skin [2]. | [Synthesis]
Example 4a: Procedure for the synthesis of (R)-2-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamide (Ia):
1. to a solution of (R)-2-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methylbutanoic acid (4a) (3.5 kg, 11.24 mol, 1.0 eq.) dissolved in 7 vol. (32.6 kg) of dichloromethane (DCM) at <30°C was added diisopropylethylamine (DIEA) (3.61 kg, 28.1 moles, 2.5 equivalents).
2. The total water content of the reaction system was adjusted to 5.5 ± 0.5% by addition of water (0.103 kg) and stirred at <30°C for at least 30 minutes.
3. cool the reaction mixture to 0±5°C and slowly add propylphosphonic anhydride solution (17.9 kg, 28.1 moles, 2.5 eq.), keeping the temperature below 20°C.
4. after stirring at 20±5°C for at least 1 hour, 2,2,2-trifluoroethylamine (1.68 kg, 16.86 mol, 1.5 eq.) was added, keeping the temperature below 20°C.
5. the reaction mixture was warmed to 25±5°C and stirred for 5 hours until the reaction was complete (confirmed by HPLC).
6. add water (17.5 kg, 5 v/v) and stir at <30°C for at least 30 min.
7. Concentrate the mixture under vacuum at <45°C using a rotary evaporator.
8. Add isopropyl acetate (1.55 kg, 0.5 v/v) and adjust pH to 7.5-8.0 with 6N NaOH solution at < 35°C.
9. Cool to 10±5°C and stir for at least 1 h. Re-adjust pH to 7.5-8.0 with 6N HCl if necessary.
10. Filter the slurry, wash the filter cake with water (10.5 kg, 3 v/v) and keep under positive nitrogen pressure for at least 30 minutes.
11. Dissolve the wet filter cake in methanol (44.7 kg, 12 v/v), add PL-BnSH MP-Resin (0.235 kg, 5% w/w) and treat for at least 12 hours at 25±5°C.
12. The mixture was filtered and the solids were washed with methanol (2.77 kg, 1 volume).
13. The filtrate is concentrated under vacuum at <50°C without drying and allowed to stand at room temperature for about 2.5 days with stirring.
14. Heat to 40°C, slowly add preheated water (56.1 kg, 45°C), keep at 45±5°C, rotate for 1 hour and further concentrate methanol.
15. Cool to 5±5°C, stir for at least 2 h. Filter the product and wash with water (10.5 kg, 3 v/v).
16. The filter cake was kept under positive pressure of nitrogen for at least 30 minutes and dried under vacuum to constant weight to give the target product (4.182 kg, white powder).
[0412] The resulting (R)-2-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methyl-N-(2,2,2-trifluoroethyl)butyramide (Ia) was analyzed by XRPD, TGS, and DSC, and the results are shown in Figures 5-7. | [in vivo]
Decernotinib (VX-509, 10, 25, or 50 mg/kg, p.o.) significantly and dose-dependently inhibits the increases in ankle diameter and paw weight occuring in response to collagen injections in rats. Decernotinib potently alleviates cartilage damage and bone resorption in rats. Decernotinib (10, 25, or 50 mg/kg, p.o., b.i.d.) suppresses ear edema in a mouse model of delayed-type hypersensitivity[1]. | [IC 50]
JAK3: 2.5 nM (Ki); JAK1: 11 nM (Ki); Tyk2: 11 nM (Ki); JAK2: 13 nM (Ki); FLT3: 1 μM (Ki); ROCK I: 1.5 μM (Ki); GSK3β: 1.8 μM (Ki); CDK2/CycA: 2.6 μM (Ki); PknB: 8 μM (IC50) | [References]
[1]. farmer lj, ledeboer mw, hoock t, et al. discovery of vx-509 (decernotinib): a potent and selective janus kinase 3 inhibitor for the treatment of autoimmune diseases. j med chem, 2015, 58(18): 7195-7216.
[2]. mahajan s, hogan jk, shlyakhter d, et al. vx-509 (decernotinib) is a potent and selective janus kinase 3 inhibitor that attenuates inflammation in animal models of autoimmune disease. j pharmacol exp ther, 2015, 353(2): 405-414. |
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