1187594-09-7 Usage
Description
Baricitinib, also known as Olumiant, is a novel small molecule that selectively inhibits Janus kinase 1 (JAK1) and Janus kinase 2 (JAK2) with excellent potency and selectivity. It is an oral, targeted synthetic disease-modifying antirheumatic drug (tsDMARD) approved by the FDA for the treatment of rheumatoid arthritis and alopecia areata. Baricitinib blocks JAK/STAT signaling, reducing cytokine release and suppressing the innate and adaptive immune systems. It has also shown promise in improving COVID-19 symptoms by suppressing the cytokine release syndrome ("cytokine storm") induced by SARS-CoV-2 infection.
Uses
Used in Pharmaceutical Industry:
Baricitinib is used as an anti-inflammatory drug for the treatment of rheumatoid arthritis and alopecia areata. It is a JAK1 and JAK2 inhibitor that modulates the immune response and reduces inflammation in these conditions.
Used in COVID-19 Treatment:
Baricitinib is used as a potential treatment for COVID-19, particularly for patients with severe symptoms. It helps in reducing the cytokine release syndrome ("cytokine storm") induced by SARS-CoV-2 infection, which can lead to severe inflammation and organ damage.
Indication and administration
It is indicated for the treatment of moderate to severe active rheumatoid arthritis in adult patients who have responded inadequately to, or who are intolerant to one or more disease-modifying anti-rheumatic drugs as monotherapy or in combination with methotrexate. Rheumatoid arthritis is a progressive autoimmune disease commonly associated with discomfort, disability, and joint damage. Throughout disease progression, the disease may further lead to joint erosions and deformities, causing premature mortality, functional impairment, and reduced quality of life[8].
In the EU[3] and Japan[4], oral baricitinib is approved (as monotherapy or in combination with methotrexate[3]) for the treatment of adults with (moderate to severe active[3]) RA who responded inadequately (to other treatments[4]), or who were intolerant of C1 DMARD[3]. The recommended dosage of baricitinib is 4 mg once daily; consideration may be given to a lower dosage of 2 mg once daily in patients who achieve sustained control of disease activity (with the higher dosage) and are eligible for dose tapering[3, 4]. The lower dosage is recommended for some patients, is appropriate for patients aged C75 years, and may also be appropriate for those with a history of chronic or recurrent infections[3]. In patients with mild or moderate hepatic impairment, no dose adjustments are required; the use of baricitinib is not recommended in patients with severe hepatic impairment[3].
Temporary or permanent discontinuation of baricitinib may be required for the management of AEs and laboratory abnormalities associated with baricitinib therapy[3, 4]. Local prescribing information should be consulted for further information, including contraindications, warnings, precautions, drug interactions and use in special patient populations.
Pharmacodynamics
Baricitinib inhibits cytokine-induced STAT3 phosphorylation in whole blood from healthy subjects. Maximal inhibition was observed at approximately 1-2 hours post dose and corresponds with the maximum observed plasma concentration (Cmax) blood levels[10].
Mean absolute neutrophil count decreased in a dose related manner reaching a nadir at 8 hours following dosing and returning to baseline 16-24 hours post-dose. In the multiple dose study, neutrophil count return to baseline within 24 hours following the final dose of study medication on Day 10 or Day 28 of repeat dosing. On the other hand, mean absolute lymphocyte count tended to increase peaking 6 hours after dosing and returning toward normal by 24 hours after dosing. Transient increases of absolute lymphocyte count reversed by 24 hours in the 10-day and 28-day repeat dose studies[10]. In the phase 3 studies for RA, increase in T cells, B cells, and NK cells were seen at week 4, while decreased T cells and NK cells and increased B cells were seen at week 12 and 24 in patients taking baricitinib[11]. These changes were generally within normal ranges. Decreased NK cell count did not appear to be associated with an increased incidence of infection.
In vitro, baricitinib demonstrates excellent potency in cell-based assays. Baricitinib inhibited IL-6 stimulated phosphorylation of STAT3 and subsequent production of MCP-1 with IC50 value of 44nM and 40nM, respectively in PBMC. This effect was not due to general cytotoxicity. Baricitinib also potently inhibited the phosphorylation of STAT proteins and the production of pathogenic cytokines such as IL-17 and IL-22 in T cells[9]. In our experiments, both IFN-α and IL-6 induced phosphorylation of STAT1, STAT3 and STAT4 in human CD4+ T cells. IL-12 induced phosphorylation of STAT4. IL-21 induced phosphorylation of STAT3 and STAT4. Baricitinib inhibited the phosphorylation of STAT1, STAT3 and STAT4 induced by IFN-α, IL-6, IL-12 and IL-21[12].
Safety
In RA-BEACON study[14], which enrolled 527 adult patients with moderately to severely active RA who have had an insufficient response to or are intolerant to at least 1 biologic TNF-α inhibitor and were taking background csDMARD therapy, more patients experienced treatment emergent adverse event (TEAE) in the baricitinib groups compared to placebo. Adverse event-ratio through 24 weeks was higher for patients receiving the 2 mg dose (71%) of baricitinib and those receiving the 4 mg dose (77%) than for patients receiving placebo (64%), including infections (44% and 40%, vs. 31%). Mild or moderate, non-serious infections of the upper respiratory tract appeared to contribute substantially to any imbalance. These events were also associated with an increase in brief, temporary interruptions of study drug in the baricitinib groups. The rates of serious adverse events (SAE) were 4%, 10%, and 7% in the three groups, respectively. The proportions of patients with an SAE were similar across treatment groups. Few malignancies were seen; 2 non-melanoma skin cancers in the baricitinib 4 mg group, with no solid organ, hematologic, or other malignancies reported. Two positively adjudicated treatment-emergent major adverse cardiovascular events (MACE) occurred: 1 myocardial infarction (baricitinib 4 mg) and 1 basilar artery thrombosis (baricitinib 4 mg) that was also the only death during the study. No patient experienced a gastrointestinal perforation. Baricitinib was associated with a small reduction in neutrophil levels and increases in serum creatinine and LDL cholesterol levels. Very few patients permanently discontinued study drug as a result of a treatment emergent laboratory abnormality in the baricitinib groups.
References
Shi JG, Chen X, Lee F, et al. The pharmacokinetics, pharmacodynamics, and safety of baricitinib, an oral JAK 1/2 inhibitor, in healthy volunteers. J Clin Pharmacol. 2014; 54(12):1354–61.
Two new drugs for rheumatoid arthritis. Drug Ther Bull. 2017;55(9):102–5.
European Medicines Agency. Olumiant (baricitinib) film-coated tablets: EU summary of product characteristics. 2017. http://www.ema.europa.eu/.
Eli Lilly. Olumiant (baricitinib): Japanese prescribing information 2017. https://www.pmda.go.jp.
O'Shea JJ, Plenge R. JAK and STAT signaling molecules in immunoregulation and immune-mediated disease. Immunity. 2012; 36(4):542-550.
Darnell JE, Jr., Kerr IM, Stark GR. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science. 1994; 264(5164):1415-1421.
Fridman J, Scherle P, Collins R et al. Selective inhibition of JAK1 and JAK2 is efficacious in rodent models of arthritis: preclinical characterization of INCB028050. J Immunol. 2010; 184(9): 5298-5307.
Ni H, Moe S, Myint KT, Htet A: Oral janus kinase inhibitor for the treatment of rheumatoid arthritis: to facitinib. ISRN Rheumatol. 2013 Jul 21;2013:357904. doi: 10.1155/2013/357904. eCollection 2013.
Fridman J, Scherle P, Collins R et al. Selective inhibition of JAK1 and JAK2 is efficacious in rodent models of arthritis: preclinical characterization of INCB028050. J Immunol. 2010;184(9):5298-5307.
Shi JG, Chen X, Lee F et al. The pharmacokinetics, pharmacodynamics, and safety of baricitinib, an oral JAK 1/2 inhibitor, in healthy volunteers. J Clin Pharmacol. 2014;54(12):1354-1361.
Emery P, McInnes I, Genovese M et al. Characterization of Changes in Lymphocyte Subsets in Baricitinib-Treated Patients with Rheumatoid Arthritis in Two Phase 3 Studies. ACR/ARHP Annual Meeting. ABSTRACT NUMBER: 1047. 2015 Nov 8, San Francisco
Kubo S, Nakayamada S, Nakano N, Tanaka Y. Baricitinib targets the type I IFN/STAT-mediated activities of human T cells and dendritic cells. EULAR congress. ABSTRACT NUMBER: THU0203. 2016, London
Posada MM, Cannady EA, Payne CD, et al. Prediction of transporter- mediated drug–drug interactions for baricitinib. Clin Transl Sci. 2017;10(6):509–19.
van Der Heijde D, Schiff M, Tanaka Y, et al. Low rates of radiographic progression of structural joint damage over 2 years of baricitinib treatment in patients with rheumatoid arthritis[abstract no. FRI0087]. Ann Rheum Dis. 2017;76(Suppl 2):510–1.
References
1) Fridman?et al.?(2010),?Selective Inhibition of JAK1 and JAK2 Is Efficacious in Rodent Models of Arthritis: Preclinical Characterization of INCB028050; J. Immunol. Biol.,?184?5298
2) Kubo?et al.?(2018),?Janus Kinase Inhibitor Baricitinib Modulates Human Innate and Adaptive Immune System; Front. Immunol.,?9?1510
3) Cantini?et al.?(2020),?Baricitinib Therapy in COVID-19: A Pilot Study on Safety and Clinical Impact; J. Infect.,?81?318
Clinical Use
Janus kinase inhibitor:
Treatment of moderate to severe active rheumatoid
arthritis
Enzyme inhibitor
This selective, ATP-competitive protein kinase inhibitor (FW = 371.42 g/mol; CAS 1187594-09-7; Solubility: 70 mg/mL DMSO, <1 mg/mL H2O), also known by its code names LY3009104 and INCB028050 as well as its systematic name 1-(ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]-pyrimidin-4-yl)- 1H-pyrazol-1-yl]-3-azetidineacetonitrile, targets JAK1 and JAK2, with respective IC50 values of 5.9 nM and 5.7 nM, showing little effect on JAK3 (IC50 = 560 nM). In cell-based assays, INCB028050 proved to be a potent inhibitor of JAK signaling and function. Primary Mode of Inhibitory Action: Janus kinases JAK1, JAK2, JAK3, and the related enzyme TYK2 are critical components of signaling mechanisms used by many cytokines and growth factors, including several that are elevated in patients with RA. Cytokines such as interleukin-6, -12 and -23 and both type 1 and type 2 interferons signal through these pathways. JAK-dependent cytokines have been implicated in the pathogenesis of inflammatory and autoimmune diseases, suggesting that JAK inhibitors may be useful for the treatment of a broad range of inflammatory conditions. At concentrations <50 nM, baricitinib inhibits intracellular signaling of multiple proinflammatory cytokines including IL-6 and IL-23. Significant efficacy, as assessed by improvements in clinical, histologic and radiographic signs of disease, was achieved in a rat adjuvant arthritis model with baricitinib providing partial and/or periodic inhibition of JAK1/JAK2 and no inhibition of JAK3. Such findings suggest that fractional inhibition of JAK1 and JAK2 may be sufficient for significant pharmacological activity in autoimmune diseases, such as rheumatoid arthritis. A related JAK inhibitor, Tofacitinib, is approved in the U.S. for the treatment of RA. Target(s): Baricitinib shows moderate (~10x) selectivity against Tyk2 (IC50 = 53 nM) and marked selectivity over the unrelated c-Met (IC50 > 10,000 nM) and Chk2 (IC50 > 1,000 nM) kinases as well as ~100x higher IC50 values against Abl, Akt1, AurA, AurB, CDC2, CDK2, CDK4, CHK2, c-kit, EGFR, EphB4, ERK1, ERK2, FLT-1, HER2, IGF1R, IKKα, IKKβ, JNK1, Lck, MEK1, p38α, p70S6K, PKA, PKCα, Src, and ZAP70.
Drug interactions
Potentially hazardous interactions with other drugs
Avoid with other DMARDs due to increased
immunosuppression. Use with care with other immunosuppressants.
Antipsychotics: increased risk of agranulocytosis
with clozapine - avoid.
Live vaccines: avoid concomitant use
Metabolism
Baricitinib is hepatically metabolism by CYP3A4, <10%
of the dose identified as undergoing biotransformation.
No metabolites were detected in plasma.
In a clinical pharmacology study, baricitinib was excreted
mainly as the unchanged active substance in urine (69%)
and faeces (15%) and only 4 minor oxidative metabolites
were identified (3 in urine; 1 in faeces) constituting
approximately 5% and 1% of the dose, respectively
Check Digit Verification of cas no
The CAS Registry Mumber 1187594-09-7 includes 10 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 7 digits, 1,1,8,7,5,9 and 4 respectively; the second part has 2 digits, 0 and 9 respectively.
Calculate Digit Verification of CAS Registry Number 1187594-09:
(9*1)+(8*1)+(7*8)+(6*7)+(5*5)+(4*9)+(3*4)+(2*0)+(1*9)=197
197 % 10 = 7
So 1187594-09-7 is a valid CAS Registry Number.
1187594-09-7Relevant articles and documents
Preparation method of baricitinib
-
, (2021/06/06)
The invention discloses a preparation method of baricitinib. The preparation method comprises the following steps: taking 4-chloropyrrolopyrimidine as an initial raw material, protecting amino with Boc anhydride, then carrying out substitution reaction with malondialdehyde dimethyl acetal, further adjusting the acid, and adding hydrazine hydrate for cyclization to obtain a compound 4; carrying out addition reaction on the compound 5 and 2-[1-(ethylsulfonyl)-3-azacyclobutyl] acetonitrile (compound 5), and removing an amino protecting group by using trifluoroacetic acid to obtain baricitinib. According to the substitution cyclization reaction of the method, a reflux reaction in an oxygen environment in the reaction process is avoided, the reaction safety is improved, the reaction selectivity is also improved, other impurities difficult to remove are avoided, the product purity is high, and the yield is high.
Synthesis and Characterization of Compounds Potentially Related to the Janus Kinase Inhibitor Baricitinib
Dasari,Seelam,Jayachandra,Vadali,Yerva,Tondepu,Gadakar
, p. 1569 - 1574 (2019/12/28)
Nine compounds potentially related to the Janus kinase inhibitor Baricitinib have been identified, synthesized by conventional methods, and characterized by IR, 1H and 13C NMR, and mass spectral data.
Baricitinib, novel crystal form of Baricitinib phosphate and preparation methods of Baricitinib and novel crystal form of Baricitinib phosphate
-
Paragraph 0053-0054, (2018/09/08)
The invention provides a Baricitinib III crystal form, a Baricitinib phosphate crystal form D, and preparation methods of the Baricitinib III crystal form and the Baricitinib phosphate crystal form D.An X-ray diffraction pattern of the Baricitinib III crystal form has diffraction peaks at diffraction angle 2 theta: 4.238 +/- 0.2 degree, 12.558 +/- 0.2 degree, 16.747 +/- 0.2 degree, 25.194 +/- 0.2degree, and 29.466 +/- 0.2 degree. An X-ray diffraction pattern of the Baricitinib phosphate crystal form D has diffraction peaks at diffraction angle 2 theta: 3.217 +/- 0.2 degree, 12.609 +/- 0.2 degree, 17.825 +/- 0.2 degree, 19.665 +/- 0.2 degree, 20.617 +/- 0.2 degree, and 22.055 +/- 0.2 degree. The crystal forms prepared through the methods of the invention have advantages of good comprehensive performances. Therefore, the curative effect and the possibility of development of the medicine kind can be improved, which is of vital importance to clinical applications of the Baricitinib medicine.