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Upadacitinib

Introduction
Product Name
Upadacitinib
CAS No.
1310726-60-3
Chemical Name
Upadacitinib
Synonyms
ABT-494;(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;upatinib;Upadacitinib (ABT-494);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;CS-2730;Upadacitinb;Upadacitinib
CBNumber
CB53121345
Molecular Formula
C17H19F3N6O
Formula Weight
380.37
MOL File
1310726-60-3.mol
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Upadacitinib Property

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
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Hazard and Precautionary Statements (GHS)

Symbol(GHS)
Signal word
Warning
Hazard statements

H302Harmful if swallowed

Precautionary statements

P280Wear protective gloves/protective clothing/eye protection/face protection.

P305+P351+P338IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continuerinsing.

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N-Bromosuccinimide Price

Cayman Chemical
Product number
29706
Product name
Upadacitinib
Packaging
5mg
Price
$116
Updated
2024/03/01
Cayman Chemical
Product number
29706
Product name
Upadacitinib
Packaging
25mg
Price
$381
Updated
2024/03/01
Cayman Chemical
Product number
29706
Product name
Upadacitinib
Packaging
1mg
Price
$32
Updated
2024/03/01
Cayman Chemical
Product number
29706
Product name
Upadacitinib
Packaging
10mg
Price
$169
Updated
2024/03/01
TRC
Product number
U800075
Product name
Upadacitinib
Packaging
1mg
Price
$300
Updated
2021/12/16
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Upadacitinib Chemical Properties,Usage,Production

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.

Description

Upadacitinib is a JAK1 inhibitor (IC50 = 47 nM). It is selective for JAK1 over JAK3 and tyrosine kinase 2 (Tyk2; IC50s = 2,304 and 4,690 nM, respectively), as well as a panel of 83 additional kinases at 1 μM, but does inhibit JAK2, Rho-associated kinase I (ROCK1), and ROCK2 (IC50s = 120, 920, and 430 nM, respectively). Upadacitinib decreases cytokine-induced STAT phosphorylation in a variety of human cells with IC50 values ranging from 1.6 to 649 nM. It reduces M. tuberculosis-induced paw swelling and bone erosion in a rat model of arthritis when administered at doses of 1, 3, and 10 mg/kg twice per day for 17 days. Formulations containing upadacitinib have been used in the treatment of rheumatoid arthritis.

Characteristics

Class: non-receptor tyrosine kinase
Treatment: psoriatic arthritis, rheumatoid arthritis
Elimination half-life = 6–16 h
Protein binding = 52%

Uses

Upadacitinib 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. It is used to treat moderate to severely active rheumatoid arthritis, active psoriatic arthritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis (a type of arthritis in the spine) with objective signs of swelling, moderate to severe ulcerative colitis, and moderate to severe Crohn's disease in patients who have taken other medicines (eg, methotrexate) that did not work well. It is also used to treat moderate to severe atopic dermatitis (eczema) in patients who have taken other medicines that did not work well and whose condition is not well controlled with other treatments or in patients who cannot tolerate these treatments.  It is also used to treatpsoriatic arthritis, axial SpA and Giant Cell Arteritis and Takayasu Arteritis.

brand name

Upadacitinib is marketed under the brand name RINVOQ for oral administration.

Biological Activity

Upadacitinib 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 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

Upadacitinib Preparation Products And Raw materials

Raw materials

Preparation Products

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View Lastest Price from Upadacitinib manufacturers

hebei hongtan Biotechnology Co., Ltd
Product
Upadacitinib 1310726-60-3
Price
US $30.00/kg
Min. Order
1kg
Purity
98%
Supply Ability
2000kg
Release date
2024-05-17
Sinoway Industrial co., ltd.
Product
Upadacitinib 1310726-60-3
Price
US $0.00-0.00/Kg/Bag
Min. Order
1Kg/Bag
Purity
0.99
Supply Ability
20 tons
Release date
2023-11-03
WUHAN FORTUNA CHEMICAL CO., LTD
Product
Upadacitinib 1310726-60-3
Price
US $0.00/g
Min. Order
1g
Purity
98%min
Supply Ability
1000g
Release date
2021-10-15

1310726-60-3, UpadacitinibRelated Search:

Baricitinib Ibrutinib tert-butyl 5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate [2-[(3R,4S)-4-ethyl-1-[(phenylmethoxy)carbonyl]-3-pyrrolidinyl]-2-oxoethyl]dimethyl-Sulfoxonium inner salt (3R,4S)-3-(2-Bromoacetyl)-4-ethyl-1-pyrrolidinecarboxylic acid phenylmethyl ester AZD-9291 Nintedanib Ethanesulfonate Salt Olaparib Vandetanib 3-(1-Methyl-1H-pyrazol-4-yl)-5-oxo-N-(2-pyridinylmethyl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-7-methanesulfonamide 2-[[(2E)-3-(2-NAPHTHALENYL)-1-OXO-2-BUTEN-1-YL]AMINO]BENZOIC ACID Q-VD-OPh hydrate N-(2-(4'-cyanobiphenyl-4-yl)propyl)propane-2-sulfonaMide H3B-6527 1-((2S,5R)-5-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one Senexin B 1,3-Pyrrolidinedicarboxylic acid, 4-ethyl-, 3-ethyl 1-(phenylmethyl) ester 1,3-Pyrrolidinedicarboxylic acid, 4-ethyl-, 1-(phenylmethyl) ester

  • Upadacitinib
  • ABT-494
  • ABT-494(Upadacitinib) free base
  • Upadacitinib (ABT-494)
  • ABT-494 (Upadacitinib)
  • Upadacitinib (Rinvoq)
  • ABT-494; ABT494; ABT 494
  • CS-2730
  • (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
  • (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
  • 1-Pyrrolidinecarboxamide, 3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)-, (3S,4R)-
  • benzyl (4S)-3-(N-(ethoxycarbonyl)-N-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)glycyl)-4-ethylpyrrolidine-1-carboxylate
  • Upacidatinib
  • upatinib
  • (3S,4R)-3-Ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)-1-pyrrolidinecarboxamide
  • (3S,4R)-3-ethyl-4-(1,5,7,10-tetrazatricyclo[7.3.0.02,6]dodeca-2(6),3,7,9,11-pentaen-12-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide
  • Upadacitinb
  • Upatinib anhydrous substance
  • Upadacitinib in Stock
  • 1310726-60-3
  • API
  • API