| Identification | Back Directory | [Name]
Upadacitinib | [CAS]
1310726-60-3 | [Synonyms]
ABT-494
CS-2730
Upadacitinib
Upadacitinib (Rinvoq)
Upadacitinib (ABT-494)
ABT-494 (Upadacitinib)
ABT-494; ABT494; ABT 494
ABT-494(Upadacitinib) free base
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide
benzyl (4S)-3-(N-(ethoxycarbonyl)-N-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)glycyl)-4-ethylpyrrolidine-1-carboxylate
1-Pyrrolidinecarboxamide, 3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)-, (3S,4R)-
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, Upadacitinib | [EINECS(EC#)]
213-161-9 | [Molecular Formula]
C17H19F3N6O | [MDL Number]
MFCD30502663 | [MOL File]
1310726-60-3.mol | [Molecular Weight]
380.37 |
| Questions And Answer | Back Directory | [Introduction]
Upadacitinib (ABT-494) is a Janus kinase 1 (JAK1) inhibitor currently being developed by AbbVie for the treatment of rheumatoid arthritis (RA), Crohn’s disease, ulcerative colitis, atopic dermatitis, and psoriatic arthritis. It is also being investigated as a potential treatment for people with active ankylosing spondylitis (AS).
AS is an inflammatory, progressive autoimmune disease that affects the joints of the spine. As the disease progresses, calcium deposits form where ligaments attach to the bones that form the spine, leading to reduced flexibility of the back. |
| Chemical Properties | Back Directory | [density ]
1.56±0.1 g/cm3(Predicted) | [storage temp. ]
Store at -20°C | [solubility ]
DMSO:42.67(Max Conc. mg/mL);112.17(Max Conc. mM)
DMSO:PBS (pH 7.2) (1:1):0.5(Max Conc. mg/mL);1.31(Max Conc. mM)
DMF:30.0(Max Conc. mg/mL);78.87(Max Conc. mM)
Ethanol:76.0(Max Conc. mg/mL);199.8(Max Conc. mM) | [form ]
A crystalline solid | [pka]
11.89±0.60(Predicted) | [color ]
White to off-white | [InChI]
InChI=1S/C17H19F3N6O/c1-2-10-7-25(16(27)24-9-17(18,19)20)8-11(10)13-5-22-14-6-23-15-12(26(13)14)3-4-21-15/h3-6,10-11,21H,2,7-9H2,1H3,(H,24,27)/t10-,11+/m1/s1 | [InChIKey]
WYQFJHHDOKWSHR-MNOVXSKESA-N | [SMILES]
N1(C(NCC(F)(F)F)=O)C[C@H](C2N3C4C=CNC=4N=CC3=NC=2)[C@H](CC)C1 |
| Hazard Information | Back Directory | [Description]
Upadacitinib (ABT-494) (1310726-60-3) is a JAK1 selective inhibitor being investigated to treat rheumatoid arthritis, Crohn's disease, ulcerative colitis, atopic dermatitis, psoriatic arthritis, axial SpA Giant Cell Arteritis and Takayasu Arteritis.
| [Characteristics]
Class: non-receptor tyrosine kinase
Treatment: psoriatic arthritis, rheumatoid arthritis
Elimination half-life = 6–16 h
Protein binding = 52%
| [Uses]
Upadacitinib(1310726-60-3) also known as ABT-494, is a potent and selective Janus kinase (JAK) 1 inhibitor being developed for the treatment of several autoimmune disorders, Janus kinase inhibitors for rheumatoid arthritis.
| [Brand name]
Upadacitinib is marketed under the brand name RINVOQ for oral administration. | [Biological Activity]
Upadacitinib(1310726-60-3) is a potent, orally active and selective Janus kinase 1 (JAK1) inhibitor (IC50=43 nM). Upadacitinib displays approximately 74 fold selective for JAK1 over JAK2 (200 nM) in cellular assays dependent on specific, relevant cytokines. Upadacitinib can be used for several autoimmune disorders research. In vivo, Upadacitinib inhibited paw swelling and bone destruction in a rat model of arthritis.
| [Mechanism of action]
The Janus kinases (JAKs) are a family of cytoplasmic tyrosine kinases whose function is to transduce cytokine-mediated signals via the JAK-STAT pathway. There are four JAK subtypes, each of which has overlapping receptor responsibilities. Inhibitors of this enzyme family (jakinibs) have shown efficacy in treating certain inflammatory and autoimmune diseases such as rheumatoid arthritis and Crohn's disease. However, the first generation of these drugs, tofacitinib and ruxolitinib, lacked subtype selectivity, affecting JAK1/JAK3 and JAK1/JAK2 respectively. This has led to dose-limiting side effects in this otherwise promising class of drugs. Upadacitinib is a second generation Janus kinase inhibitor that is selective for the JAK1 subtype of this enzyme over the JAK2 (74-fold), JAK3 (58-fold) and tyrosine kinase 2 subtypes. | [Clinical Use]
Upadacitinib(1310726-60-3) is indicated for the treatment of moderate to severe active rheumatoid arthritis in adults who have responded inadequately to, or who are intolerant to one or more disease-modifying antirheumatic drugs (DMARDs). Upadacitinib may be used as monotherapy or in combination with methotrexate.
| [Side effects]
Common side effects are upper respiratory tract infections such as common cold and sinus infections (13.5% of patients in studies), nausea (3.5%), cough (2.2%), fever, and increased liver enzymes. Serious side effects include infections, including life-threatening ones, such as pneumonia, cellulitis, tuberculosis, as well as shingles and other herpes infections. | [Synthesis]
To a solution of (3S,4R)-3-ethyl-4-(3-tosyl-3H-imidazo[l,2-a]pyrrolo[2,3-e]pyrazin-8-yl)- N-(2,2,2-trifluoroethyl)pyrrolidine-l-carboxamide (10 g) in tetrahydrofurane (50 ml_), a 10% solution of sodium hydroxide in water (15 ml) was added and heated to 50??C. The reaction mixture was stirred for 5 hours and cooled to 25??C. A saturated solution of sodium chloride (100 ml_) was added to the reaction mixture and extracted with dichloromethane (100 ml). The organic phase was separated and washed with water (100 ml_). An 2.5 % aqueous solution of HCI (100 ml) was added and stirred for 30 minutes. The organic phase was removed and the resultant acid aqueous phase was extracted with dichloromethane (100 ml). The final aqueous phase was cooled down to 0/5 ??C and a 10% solution of NaOH was charged until pH 10/12. The resultant suspension was filtered and washed with water (2 x 50 ml_). The cake was drained and dried at 30/40??C under vacuum to give an almost white amorphous solid. Yield: 80%. 1 H NMR (400MHz, d-DMSO) 612.27 (s,1H), 8.58 (s,1H), 7.47-7.43 (m,2H), 7.00-6.94 (m,2H), 4.38 -4.33 (m,1H), 3.92-3.67 (m,5H), 3.33-3.25 (m,1 H), 2.59-2.54 (m,1 H), 1.14-1.08 (m,1 H), 0.86-0.78 (m, 1H), 0.65-0.62 (m, 3H). | [Metabolism]
Upadacitinib displays a dose-proportional pharmacokinetic profile over the therapeutic dose range. Following oral administration, the median time to reach Cmax (Tmax) ranges from 2 to 4 hours. The steady-state plasma concentrations of upadacitinib are reached within 4 days following multiple once-daily administrations, with minimal accumulation. Food intake has no clinically relevant effect on the AUC, Cmax, and Cmin of upadacitinib from the extended-release formulation. Upadacitinib metabolism is mainly mediated by CYP3A4, with a potential minor contribution from CYP2D6. Administration of strong CYP3A inhibitors increases upadacitinib AUC by 75% and Cmax by 70%, while strong inducers of CYP3A reduce upadacitinib plasma exposures by approximately half[1]. | [References]
[1] Mohamed-Eslam F. Mohamed. “Upadacitinib: Mechanism of action, clinical, and translational science.” Cts-Clinical and Translational Science 17 1 (2023). | [storage]
Store at -20°C |
|
|