Upadacitinib
[CAS# 1310726-60-3]

Identification

• Classification: API >> Other chemicals
• Name: Upadacitinib
• Synonyms: (3S,4R)-3-Ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)-1-pyrrolidinecarboxamide; ABT 494
• Molecular Formula: C₁₇H₁₉F₃N₆O
• Molecular Weight: 380.37
• CAS Registry Number: 1310726-60-3
• SMILES: CC[C@@H]1CN(C[C@@H]1C2=CN=C3N2C4=C(NC=C4)N=C3)C(=O)NCC(F)(F)F

Properties

• Density: 1.56±0.1 g/cm³ (20 ºC 760 Torr), Calc.^*
• Index of refraction: 1.678 (Calc.)^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Hazard Symbols: GHS07 Warning
• Hazard Statements: H302
• Precautionary Statements: P280-P305+P351+P338

Discovory and Applicatios

Upadacitinib is an oral, small-molecule Janus kinase (JAK) inhibitor developed for the treatment of various autoimmune and inflammatory diseases. It selectively inhibits JAK1, a member of the JAK family of intracellular tyrosine kinases involved in cytokine receptor signaling pathways. JAKs play a critical role in the immune system by transmitting signals from various cytokine receptors to signal transducer and activator of transcription (STAT) proteins, which then regulate gene expression. Dysregulation of this pathway is implicated in several immune-mediated conditions.

The discovery of upadacitinib was part of a broader effort to develop selective JAK inhibitors with improved safety profiles compared to earlier, less selective compounds. It was developed by AbbVie Inc., following research into ways to modulate immune responses in a targeted manner while reducing adverse effects associated with broader JAK inhibition. Unlike pan-JAK inhibitors, upadacitinib was designed to preferentially inhibit JAK1 over other JAK isoforms, particularly JAK2 and JAK3, to minimize off-target effects related to hematopoiesis and immune cell development.

Upadacitinib received its first regulatory approval from the U.S. Food and Drug Administration (FDA) in 2019 for the treatment of moderate to severe rheumatoid arthritis (RA) in adult patients who had an inadequate response or intolerance to one or more tumor necrosis factor (TNF) inhibitors. It was subsequently approved for several additional indications, including psoriatic arthritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis, atopic dermatitis, ulcerative colitis, and Crohn’s disease, depending on the country and region.

The clinical development program for upadacitinib included multiple Phase III trials under the SELECT program, which demonstrated the drug’s efficacy and safety across various autoimmune disorders. These studies showed significant improvements in clinical response, patient-reported outcomes, and disease activity scores compared to placebo and some active comparators. Notably, in atopic dermatitis and ulcerative colitis, upadacitinib has demonstrated high rates of symptom control and mucosal healing, respectively, offering a new option for patients with moderate to severe disease activity.

Upadacitinib is administered orally, typically once daily, and is available in both immediate-release and extended-release formulations. It undergoes hepatic metabolism primarily via cytochrome P450 enzyme CYP3A4, and its pharmacokinetics support a convenient dosing schedule. The drug's efficacy is based on its ability to suppress pro-inflammatory cytokine signaling, including interleukin (IL)-6, IL-12, IL-23, and interferon-γ, which are involved in the pathogenesis of autoimmune diseases.

Common side effects of upadacitinib include upper respiratory tract infections, nausea, headache, increased liver enzymes, and elevated creatine phosphokinase levels. More serious risks include opportunistic infections, herpes zoster, thromboembolic events, and malignancies. As with other JAK inhibitors, its use requires careful patient selection and monitoring, especially in individuals with risk factors for serious infections or cardiovascular disease. Regulatory agencies have issued warnings regarding the long-term safety of JAK inhibitors, leading to label updates and risk management strategies.

Upadacitinib represents an advancement in the management of autoimmune diseases by offering a targeted approach to immune modulation. Its selectivity for JAK1 allows it to achieve therapeutic efficacy while potentially reducing the risks associated with broader JAK inhibition. It continues to be studied in various clinical contexts and has become an important option in the treatment landscape for chronic inflammatory conditions.

In summary, upadacitinib is a selective JAK1 inhibitor developed for the treatment of a range of autoimmune diseases. Its discovery and development reflect advances in precision immunology, and its approval has provided new therapeutic avenues for patients with inadequate response to conventional treatments.

References

2019. Clinical efficacy of new JAK inhibitors under development. Just more of the same? Rheumatology (Oxford, England), 58(Suppl 1).
DOI: 10.1093/rheumatology/key256

2020. Critical Assessment of Pharmacokinetic Drug�Drug Interaction Potential of Tofacitinib, Baricitinib and Upadacitinib, the Three Approved Janus Kinase Inhibitors for Rheumatoid Arthritis Treatment. Drug Safety, 43(7).
DOI: 10.1007/s40264-020-00938-z

2021. Upadacitinib improves PsA in phase III trial. Nature Reviews. Rheumatology, 17(6).
DOI: 10.1038/s41584-021-00617-y