Tofacitinib citrate

Category	Influenza Virus
CAS	540737-29-9
Description	Tofacitinib (trade name Xeljanz, formerly tasocitinib, CP-690550) is a drug discovered and developed by Pfizer. It is currently approved for the treatment of rheumatoid arthritis (RA) in the United States and is being studied for treatment of psoriasis, inflammatory bowel disease, and other immunological diseases, as well as for the prevention of organ transplant rejection. (source: http://en.wikipedia.org/wiki/Tofacitinib).

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Product Information

Synonyms	CP-690550; CP 690550; CP690550; Tofacitinib; tasocitinib.
IUPAC Name	2-hydroxypropane-1,2,3-tricarboxylic acid;3-[(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl]-3-oxopropanenitrile
Molecular Weight	504.5
Molecular Formula	C22H28N6O8
Canonical SMILES	CC1CCN(CC1N(C)C2=NC=NC3=C2C=CN3)C(=O)CC#N.C(C(=O)O)C(CC(=O)O)(C(=O)O)O
InChI	InChI=1S/C16H20N6O.C6H8O7/c1-11-5-8-22(14(23)3-6-17)9-13(11)21(2)16-12-4-7-18-15(12)19-10-20-16;7-3(8)1-6(13,5(11)12)2-4(9)10/h4,7,10-11,13H,3,5,8-9H2,1-2H3,(H,18,19,20);13H,1-2H2,(H,7,8)(H,9,10)(H,11,12)/t11-,13+;/m1./s1
InChIKey	SYIKUFDOYJFGBQ-YLAFAASESA-N
Melting Point	198-202 °C (dec.)
Purity	98%
Solubility	In Vitro: DMSO : ≥ 122.5 mg/mL (242.82 mM) H2O : 5 mg/mL (9.91 mM; Need ultrasonic and warming)
Appearance	White to Off-white Solid
Application	Janus Kinase Inhibitors
Storage	RT
Animal Admin	Female BALB/c mice (6-8 weeks old) are used. Mice receive Tofacitinib in PEG300 (100 mg/mL) or vehicle alone (PEG300) by osmotic pump infusion (0.25 μL/hour, 28 days). Four days prior to immunization, mice are anesthetized and their dorsal surface is shaved. A one cm incision is made on the back to create a subcutaneous pocket and insert the pump. The incision site is closed with wound clips. Mice are injected weekly (i.p.) with SS1P recombinant immunotoxin (RIT; 5 μg/mouse) beginning on day 0; control mice received injections of saline alone. Every week before SS1P or vehicle immunization, 50 μL of blood is drawn to obtain serum samples. Sera are stored at -80°C until analyzed. Rats Adjuvant-induced arthritis (AIA) is induced in female Lewis rats. Rats are randomized according to hind paw volume and assigned to Tofacitinib or vehicle treatment regimens. Groups of 7-8 rats per treatment group, and normal naive rats (n=4 per group), are euthanized either 4 hours, 4 days, or 7 days after beginning treatment (days 16, 20, and 23 after immunization, respectively). Once-daily oral administration of vehicle or Tofacitinib (6.2 mg/kg) is initiated on day 16 following immunization and continued through day 23. Paw volumes are reassessed 4 and 7 days after the beginning of treatment (days 20 and 23 after immunization, respectively). For micro-computed tomography (micro-CT) imaging, as well as tartrate-resistant acid phosphatase (TRAP) staining in paw tissue, AIA is induced in a separate cohort of Lewis rats.
Complexity	716
Exact Mass	504.19686187
In Vitro	Tofacitinib (CP-690550) citrate binds potentially at JAK3 and JAK2 as 2.2 nM and 5 nM (Kd). The report includes additional binding for Tofacitinib at Camk1 (Kd of 5,000 nM), DCamkL3 (Kd of 4.5 nM), Mst2 (Kd of 4,300 nM), Pkn1 (Kd of 200 nM), Rps6ka2 (Kin.Dom.2-C-terminal) (Kd of 1,400 nM), Rps6ka6 (Kin.Dom.2-C-terminal) (Kd of 1,200 nM), Snark (Kd of 420 nM), Tnk1 (Kd of 640 nM) and Tyk2 (Kd of 620 nM). K562, KCL22, and THP-1 cells are exposed to different doses of Imatinib (IMA) or JAK inhibitors for 72 h to quantify the effects of tyrosine kinase inhibitor (TKI) activity. Cell growth inhibition is then evaluated using the MTT assay. The proliferation of K562 and KCL22 cells, but not THP-1 cells, is inhibited by IMA in a concentration-dependent manner. The IC50 value of IMA is 0.28 µM for K562 and 0.17 µM for KCL22. Although treatment with Tofacitinib (TOF) or Ruxolitinib (RUX) alone does not suppress cell proliferation, both Tofacitinib and Ruxolitinib make the K562 and KCL22 more sensitive to IMA.
In Vivo	Animals that are treated with Tofacitinib show a significantly lower production of anti-drug antibodies (ADAs) compare with PEG-treated control mice (for five weeks after initial immunization, p<0.01, n=8). Moreover ADAs become detectable earliest on day 28. A difference of 1000- to 200-fold in titers to SS1P is apparent from days 21 through 35, respectively. Compare to SS1P, mice injected with keyhole limpet hemocyanin (KLH) generate a more rapid antibody response. Yet, the administration of Tofacitinib reduces anti-KLH titers compare to controls (p<0.05 on day 21, p<0.01 on day 28, respectively, n=5). Reductions in titers ranged from 5000- to 250-fold from days 21 through 28, respectively. Based on previous dose-response studies, a daily dose of Tofacitinib of 6.2 mg/kg is selected to provide 80% inhibition of hind paw volume and plasma exposure capable of suppressing the JAK1 and JAK3 signaling pathways for >4 hours.
PSA	221.04000
Target	JAK3:1 nM (IC50) JAK2:20 nM (IC50) JAK1:112 nM (IC50) Rock-II:3400 nM (IC50) Lck:3870 nM (IC50)