WARNING: This product is for research use only, not for human or veterinary use.
Hodoodo CAT#: H522580
CAS#: 1310726-60-3 (free base)
Description: Upadacitinib, also known as ABT-494, is a potent and selective JAK inhibitors in development for rheumatoid arthritis. ABT-494 is approximately 74 fold selective for Jak1 over Jak2 in cellular assays dependent on specific, relevant cytokines. ABT-494 demonstrates efficacy in rat arthritis models. Preliminary evidence suggests that compared to tofacitinib, ABT-494 may spare Jak2 and Jak3 dependent signaling.
Hodoodo Cat#: H522580
Name: Upadacitinib
CAS#: 1310726-60-3 (free base)
Chemical Formula: C17H19F3N6O
Exact Mass: 380.16
Molecular Weight: 380.375
Elemental Analysis: C, 53.68; H, 5.04; F, 14.98; N, 22.09; O, 4.21
Related CAS #: 1310726-60-3 (free base) 1607431-21-9 (tartarte)
Synonym: ABT-494, ABT 494, ABT494, Upadacitinib;
IUPAC/Chemical Name: (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
InChi Key: WYQFJHHDOKWSHR-MNOVXSKESA-N
InChi Code: 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
SMILES Code: O=C(N1C[C@@H](CC)[C@@H](C2=CN=C3C=NC(NC=C4)=C4N32)C1)NCC(F)(F)F
Appearance: White to off-white solid powder
Purity: >98% (or refer to the Certificate of Analysis)
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility: Soluble in DMSO, not in water
Shelf Life: >2 years if stored properly
Drug Formulation: This drug may be formulated in DMSO
Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code: 2934.99.9001
More Info:
| Biological target: | Upadacitinib (ABT-494) is a Janus kinase 1 (JAK1) inhibitor (IC50=43 nM). |
| In vitro activity: | Consistent with the Ba/F3 cellular data, upadacitinib potently inhibited the JAK1 dependent cytokines IL-6, OSM, IL-2, and IFNγ, as measured by inhibition of STAT phosphorylation. This activity was ~ 60 fold more potent than the activity on erythropoietin signaling, a cytokine that depends exclusively upon JAK2 for signal transduction. Inhibition of IL-6 signaling in human whole blood was measured. The IC50 values for upadacitinib were 0.207 μM in the CD3+ T-cell population, and 0.078 μM in the CD14+ monocytic population. The reported IC50 values for tofactinib on IL-6 signaling in human whole blood are 0.367 μM and 0.406 μM for CD3+ T-cells and monocytes, respectively. Reference: BMC Rheumatol. 2018; 2: 23. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6390583/ |
| In vivo activity: | The normal course of AIA (adjuvant-induced arthritis) results in significant loss of bone volume that is dose dependently reduced with upadacitinib administration (Fig. 2b). Examples of destruction are shown from vehicle treated animals (Fig. 2c) with significant pitting and bone loss compared with the 10 mg/kg upadacitnib treated animals in which the surface of the bone was protected (Fig 2d). Histological endpoints were also assessed in this study. Upadacitinib administration improved synovial hypertrophy, inflammation, cartilage damage and bone erosion at the 3 and 10 mg/kg dose groups (data not shown). Similar results were observed in the rat collagen induced arthritis (CIA) model, a second preclinical model of RA (data not shown). Reference: BMC Rheumatol. 2018; 2: 23. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6390583/ |
| Solvent | Max Conc. mg/mL | Max Conc. mM | |
|---|---|---|---|
| Solubility | |||
| DMSO | 42.7 | 112.17 | |
| DMSO:PBS (pH 7.2) (1:1) | 0.5 | 1.31 | |
| DMF | 30.0 | 78.87 | |
| Ethanol | 76.0 | 199.80 |
The following data is based on the product molecular weight 380.38 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.
| Concentration / Solvent Volume / Mass | 1 mg | 5 mg | 10 mg |
|---|---|---|---|
| 1 mM | 1.15 mL | 5.76 mL | 11.51 mL |
| 5 mM | 0.23 mL | 1.15 mL | 2.3 mL |
| 10 mM | 0.12 mL | 0.58 mL | 1.15 mL |
| 50 mM | 0.02 mL | 0.12 mL | 0.23 mL |
| Formulation protocol: | 1. Parmentier JM, Voss J, Graff C, Schwartz A, Argiriadi M, Friedman M, Camp HS, Padley RJ, George JS, Hyland D, Rosebraugh M, Wishart N, Olson L, Long AJ. In vitro and in vivo characterization of the JAK1 selectivity of upadacitinib (ABT-494). BMC Rheumatol. 2018 Aug 28;2:23. doi: 10.1186/s41927-018-0031-x. PMID: 30886973; PMCID: PMC6390583. |
| In vitro protocol: | 1. Parmentier JM, Voss J, Graff C, Schwartz A, Argiriadi M, Friedman M, Camp HS, Padley RJ, George JS, Hyland D, Rosebraugh M, Wishart N, Olson L, Long AJ. In vitro and in vivo characterization of the JAK1 selectivity of upadacitinib (ABT-494). BMC Rheumatol. 2018 Aug 28;2:23. doi: 10.1186/s41927-018-0031-x. PMID: 30886973; PMCID: PMC6390583. |
| In vivo protocol: | 1. Parmentier JM, Voss J, Graff C, Schwartz A, Argiriadi M, Friedman M, Camp HS, Padley RJ, George JS, Hyland D, Rosebraugh M, Wishart N, Olson L, Long AJ. In vitro and in vivo characterization of the JAK1 selectivity of upadacitinib (ABT-494). BMC Rheumatol. 2018 Aug 28;2:23. doi: 10.1186/s41927-018-0031-x. PMID: 30886973; PMCID: PMC6390583. |
1: Onuora S. New positive results for upadacitinib in AS. Nat Rev Rheumatol. 2019 Dec 9. doi: 10.1038/s41584-019-0355-y. [Epub ahead of print] PubMed PMID: 31819253.
2: Strand V, Pope J, Tundia N, Friedman A, Camp HS, Pangan A, Ganguli A, Fuldeore M, Goldschmidt D, Schiff M. Upadacitinib improves patient-reported outcomes in patients with rheumatoid arthritis and inadequate response to conventional synthetic disease-modifying antirheumatic drugs: results from SELECT-NEXT. Arthritis Res Ther. 2019 Dec 9;21(1):272. doi: 10.1186/s13075-019-2037-1. PubMed PMID: 31815649; PubMed Central PMCID: PMC6902348.
3: Strand V, Schiff M, Tundia N, Friedman A, Meerwein S, Pangan A, Ganguli A, Fuldeore M, Song Y, Pope J. Effects of upadacitinib on patient-reported outcomes: results from SELECT-BEYOND, a phase 3 randomized trial in patients with rheumatoid arthritis and inadequate responses to biologic disease-modifying antirheumatic drugs. Arthritis Res Ther. 2019 Dec 2;21(1):263. doi: 10.1186/s13075-019-2059-8. PubMed PMID: 31791386; PubMed Central PMCID: PMC6889334.
4: Guttman-Yassky E, Thaçi D, Pangan AL, Hong HC, Papp KA, Reich K, Beck LA, Mohamed MF, Othman AA, Anderson JK, Gu Y, Teixeira HD, Silverberg JI. Upadacitinib in Adults With Moderate-to-Severe Atopic Dermatitis: 16-Week Results From a Randomized, Placebo-Controlled Trial. J Allergy Clin Immunol. 2019 Nov 28. pii: S0091-6749(19)31608-2. doi: 10.1016/j.jaci.2019.11.025. [Epub ahead of print] PubMed PMID: 31786154.
5: Upadacitinib (Rinvoq) - a new JAK inhibitor for rheumatoid arthritis. Med Lett Drugs Ther. 2019 Nov 18;61(1585):183-185. Review. PubMed PMID: 31770358.
6: Hussar DA, Helms HE. Romosozumab-aqqg, upadacitinib, and risankizumab-rzaa. J Am Pharm Assoc (2003). 2019 Nov - Dec;59(6):908-911. doi: 10.1016/j.japh.2019.09.014. PubMed PMID: 31735342.
7: van der Heijde D, Song IH, Pangan AL, Deodhar A, van den Bosch F, Maksymowych WP, Kim TH, Kishimoto M, Everding A, Sui Y, Wang X, Chu AD, Sieper J. Efficacy and safety of upadacitinib in patients with active ankylosing spondylitis (SELECT-AXIS 1): a multicentre, randomised, double-blind, placebo-controlled, phase 2/3 trial. Lancet. 2019 Dec 7;394(10214):2108-2117. doi: 10.1016/S0140-6736(19)32534-6. Epub 2019 Nov 12. PubMed PMID: 31732180.
8: Nader A, Stodtmann S, Friedel A, Mohamed MF, Othman AA. Pharmacokinetics of Upadacitinib in Healthy Subjects and Subjects With Rheumatoid Arthritis, Crohn's Disease, Ulcerative Colitis, or Atopic Dermatitis: Population Analyses of Phase 1 and 2 Clinical Trials. J Clin Pharmacol. 2019 Nov 7. doi: 10.1002/jcph.1550. [Epub ahead of print] PubMed PMID: 31701537.
9: Biggioggero M, Becciolini A, Crotti C, Agape E, Favalli EG. Upadacitinib and filgotinib: the role of JAK1 selective inhibition in the treatment of rheumatoid arthritis. Drugs Context. 2019 Oct 24;8:212595. doi: 10.7573/dic.212595. eCollection 2019. Review. PubMed PMID: 31692920; PubMed Central PMCID: PMC6821397.
10: Mohamed MF, Trueman S, Othman AA, Han JH, Ju TR, Marroum P. Development of In Vitro-In Vivo Correlation for Upadacitinib Extended-Release Tablet Formulation. AAPS J. 2019 Oct 25;21(6):108. doi: 10.1208/s12248-019-0378-y. PubMed PMID: 31654328; PubMed Central PMCID: PMC6814631.
11: Duggan S, Keam SJ. Upadacitinib: First Approval. Drugs. 2019 Nov;79(16):1819-1828. doi: 10.1007/s40265-019-01211-z. Review. PubMed PMID: 31642025.
12: A SPECIAL MEETING REVIEW EDITION: Highlights in Inflammatory Bowel Disease From the 14th Congress of ECCO: A Review of Selected Presentations From the 14th Congress of the European Crohn's and Colitis Organisation (ECCO) • March 6-9, 2019 • Copenhagen, DenmarkSpecial Reporting on:• VARSITY: A Double-Blind, Double-Dummy, Randomized Controlled Trial of Vedolizumab Versus Adalimumab in Patients With Active Ulcerative Colitis• Analyses of Data From the VISIBLE 1 and 2 Trials: Vedolizumab in Patients With Ulcerative Colitis or Crohn's Disease• Improved Endoscopic Outcomes and Mucosal Healing of Upadacitinib as an Induction Therapy in Adults With Moderately to Severely Active Ulcerative Colitis: Data From the U-ACHIEVE Study• Long-Term Safety of Vedolizumab in Ulcerative Colitis and Crohn's Disease: Final Results From the GEMINI LTS Study• Pediatric Crohn's Disease Adalimumab Level-Based Optimization Treatment (PAILOT) Randomized Controlled Trial• Maintenance Treatment With Mirikizumab, a P19-Directed IL-23 Antibody: 52-Week Results in Patients With Moderately to Severely Active Ulcerative Colitis• Real-World Effectiveness and Safety of Vedolizumab and Anti-TNF Therapy in Biologic-Naive Patients With Ulcerative Colitis or Crohn's Disease: Results From the EVOLVE Study• A Randomized, Multicenter, Double-Blind, Placebo-Controlled Study of a Targeted-Release Oral Cyclosporine Formulation in the Treatment of Mild to Moderate Ulcerative Colitis: Efficacy Results• Real-World Analyses of Patients With IBD Treated With VedolizumabPLUS Meeting Abstract Summaries With Expert Commentary by: Edward V. Loftus Jr, MDProfessor of MedicineDivision of Gastroenterology and HepatologyMayo ClinicRochester, Minnesota. Gastroenterol Hepatol (N Y). 2019 May;15(5 Suppl 2):1-24. PubMed PMID: 31632213; PubMed Central PMCID: PMC6794565.
13: Nader A, Mohamed MF, Winzenborg I, Doelger E, Noertersheuser P, Pangan AL, Othman AA. Exposure-Response Analyses of Upadacitinib Efficacy and Safety in Phase II and III Studies to Support Benefit-Risk Assessment in Rheumatoid Arthritis. Clin Pharmacol Ther. 2019 Oct 14. doi: 10.1002/cpt.1671. [Epub ahead of print] PubMed PMID: 31610021.
14: Mohamed MF, Klünder B, Lacerda AP, Othman AA. Exposure-Response Analyses for Upadacitinib Efficacy and Safety in the Crohn's Disease CELEST Study and Bridging to the Extended-Release Formulation. Clin Pharmacol Ther. 2019 Oct 8. doi: 10.1002/cpt.1668. [Epub ahead of print] PubMed PMID: 31594037.
15: Mohamed MF, Beck D, Camp HS, Othman AA. Preferential Inhibition of JAK1 Relative to JAK3 by Upadacitinib: Exposure-Response Analyses of Ex Vivo Data From 2 Phase 1 Clinical Trials and Comparison to Tofacitinib. J Clin Pharmacol. 2019 Aug 25. doi: 10.1002/jcph.1513. [Epub ahead of print] PubMed PMID: 31448433.
16: Mohamed MF, Feng T, Enejosa JV, Fisniku O, Othman AA. Effects of Upadacitinib Coadministration on the Pharmacokinetics of Sensitive Cytochrome P450 Probe Substrates: A Study With the Modified Cooperstown 5+1 Cocktail. J Clin Pharmacol. 2020 Jan;60(1):86-95. doi: 10.1002/jcph.1496. Epub 2019 Aug 5. PubMed PMID: 31378969.
17: McInnes IB, Byers NL, Higgs RE, Lee J, Macias WL, Na S, Ortmann RA, Rocha G, Rooney TP, Wehrman T, Zhang X, Zuckerman SH, Taylor PC. Comparison of baricitinib, upadacitinib, and tofacitinib mediated regulation of cytokine signaling in human leukocyte subpopulations. Arthritis Res Ther. 2019 Aug 2;21(1):183. doi: 10.1186/s13075-019-1964-1. PubMed PMID: 31375130; PubMed Central PMCID: PMC6679539.
18: Fleischmann RM, Genovese MC, Enejosa JV, Mysler E, Bessette L, Peterfy C, Durez P, Ostor A, Li Y, Song IH. Safety and effectiveness of upadacitinib or adalimumab plus methotrexate in patients with rheumatoid arthritis over 48 weeks with switch to alternate therapy in patients with insufficient response. Ann Rheum Dis. 2019 Nov;78(11):1454-1462. doi: 10.1136/annrheumdis-2019-215764. Epub 2019 Jul 30. PubMed PMID: 31362993; PubMed Central PMCID: PMC6837258.
19: Fleischmann R, Pangan AL, Song IH, Mysler E, Bessette L, Peterfy C, Durez P, Ostor AJ, Li Y, Zhou Y, Othman AA, Genovese MC. Upadacitinib Versus Placebo or Adalimumab in Patients With Rheumatoid Arthritis and an Inadequate Response to Methotrexate: Results of a Phase III, Double-Blind, Randomized Controlled Trial. Arthritis Rheumatol. 2019 Nov;71(11):1788-1800. doi: 10.1002/art.41032. Epub 2019 Aug 28. PubMed PMID: 31287230.
20: Song GG, Choi SJ, Lee YH. Comparison of the efficacy and safety of tofacitinib and upadacitinib in patients with active rheumatoid arthritis: A Bayesian network meta-analysis of randomized controlled trials. Int J Rheum Dis. 2019 Aug;22(8):1563-1571. doi: 10.1111/1756-185X.13616. Epub 2019 Jun 18. PubMed PMID: 31211506.
