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New Drug Approvals 2012 - Pt. XXV - Tofacitinib citrate (XELJANZ®)

On November 6, the FDA approved Tofacitinib citrate (Trade Name: XELJANZ®; Research code: CP-690550, ChEMBL : CHEMBL221959, PubChem: CID9926791, DrugBank: DB08183, ChemSpider: 8102425) to treat moderately to severely active Rheumatoid Arthritis (RA). It is orally administered and may be used as monotherapy agent or in combination of non-biologic DMARDs. About 1% of the world-wide population is affected by rheumatoid arthritis. RA affects predominantly women (three times more susceptible than men) and is more frequent between ages 40 and 50, but people of any age can be affected.

Other approved drugs in this commercially competitive sector include Adalimumab (Trade Name: Humira, ChEMBL: CHEMBL1201580, DrugBank: DB00051), Etanercept (Trade Name: EnbrelChEMBL: CHEMBL1201572, DrugBank: DB00005), Infliximab (Trade Name: Remicade, ChEMBL: CHEMBL1201581, DrugBank: DB00065).

IUPAC Name: 3-(4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile
Canionical Smiles: C[C@@H]1CCN(C[C@@H]1N(C)c2ncnc3[nH]ccc23)C(=O)CC#N
Standard InChi : InChI=1S/C16H20N6O/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/h4,7,10-11,13H,3,5,8-9H2,1-2H3,(H,18,19,20)/t11-,13+/m1/s1

XELJANZ is the citrate salt of tofacitinib which is an inhibitor of Janus Kinase (JAK), an intracellular tyrosine kinase which transmit signals from cytokine or growth factor-receptor interactions on the cell membrane to influence cellular processes of hematopoiesis and immune cell function. Within the signalling pathway JAKs phosphorylate and activate Signal Transducers and Activators of Transcription (STATs) which modulate intracellular activity including gene expression. JAK-STAT system is a major signalling alternative to the secondary messenger system.

XELJANZ is specifically designed to inhibit the JAK pathways, which are signalling pathways inside the cell that play an important role in the inflammation involved in RA. Tofacitinib modulates the signalling pathway and prevents the phosphorylation and activation of STATs. JAK enzymes transmit cytokine signalling through pairing of JAKs (e.g., JAK1/JAK2, JAK1/JAK3, JAK1/TyK2, JAK2/JAK2). Tofacitinib has in vitro activities against JAK1/JAK2, JAK1/JAK3 and JAK2/JAK2 combinations.

The picture on left is PDB entry: 3lxn for crystal structure for TYK2 (in Red) with CP-690550 (in Blue/Green) and the picture on right is PDBe entry: 3lxk for crystal structure for JAK3 (in Red) with CP-690550 (in Blue/Green).

Recommended dosage is 5 mg orally. It has an apparent volume of distribution of 87 L and protein binding to the drug is approximately 40%, and it's bioavailability is 74% with elimination half-life of approximately 3 hrs. Metabolism of Tofacitinb is majorly mediated by Cytochrome P450 3A4 (CYP3A4) and minor contribution from Cytochrome P450 2C19 (CYP2C19). Clearance is estimated to be 70% hepatic, 30% renal.

Full prescribing information can be found here.

License holder is Pfizer and product website is


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