ritlecitinib   Click here for help

GtoPdb Ligand ID: 9559

Synonyms: compound 11 [PMID: 28139931] | example 5 [WO2015083028] | PF-06651600 | PF06651600
Immunopharmacology Ligand
Compound class: Synthetic organic
Comment: Ritlecitinib (PF-06651600) is a potent, orally active, molecule with dual inhibitor activities. It acts as a covalent and selective inhibitor of Janus kinase 3 (JAK3) [7] (a type I inhibitor, that binds to the kinase in its ATP pocket), and it also inhibits TEC family kinases (BTK, ITK, TEC, Etk, TXK) that are involved in immune cell regulation. It has demonstrated anti-inflammatory activities in in vivo models [6]. Ritlecitinib is example 5 in a Pfizer patent that provides SAR for 343 analogues [1]. There are three crystal structures available for compounds reported in [7] with JAK3, but not for compound 11 (the PDB identifiers are 5TTV, 5TTU and 5TTS).
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2D Structure
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Physico-chemical Properties
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Hydrogen bond acceptors 5
Hydrogen bond donors 2
Rotatable bonds 4
Topological polar surface area 73.91
Molecular weight 285.16
XLogP 1.92
No. Lipinski's rules broken 0
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Canonical SMILES C=CC(=O)N1CC(CCC1C)Nc1ncnc2c1cc[nH]2
Isomeric SMILES C=CC(=O)N1C[C@@H](CC[C@@H]1C)Nc1ncnc2c1cc[nH]2
InChI InChI=1S/C15H19N5O/c1-3-13(21)20-8-11(5-4-10(20)2)19-15-12-6-7-16-14(12)17-9-18-15/h3,6-7,9-11H,1,4-5,8H2,2H3,(H2,16,17,18,19)/t10-,11+/m0/s1
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Summary of Clinical Use Click here for help
PF-06651600 has completed Phase 2 clinical trials for rheumatoid arthritis and ulcerative colitis and it has advanced to Phase 2b/3 in alopecia areata patients. Click here to link to ClinicalTrials.gov's full list of PF-06651600 trials.
Mechanism Of Action and Pharmacodynamic Effects Click here for help
Inhibition of JAK3 modulates γ-common chain cytokine pathways (e.g., IL-7, IL-9, IL-15, and IL-21) that are drivers of ulcerative colitis pathophysiology. However, unlike JAK1 inhibitors, JAK3 inhibition does not disrupt the actions of immunoregulatory cytokines (e.g., IL-10, IL-27, and IL-21) which are critical regulators of immune homeostasis in the digestive tract. Ritlecitinib-mediated inhibition of TEC family kinases impedes the functions of cytotoxic immune cells (CD8+ T cell, natural killer cells) that are involved in the pathogenesis of inflammatory bowel disease.
Clinical Trials
Clinical Trial ID Title Type Source Comment References
NCT03732807 PF-06651600 for the Treatment of Alopecia Areata Phase 2/Phase 3 Interventional Pfizer Results from this study suggest that ritlecitinib might be a suitable systermic treatment option for alopecia areata. It was effective and well tolerated, with similar rates of adverse events in the ritlecitinib and placebo groups. 3
NCT02958865 Study to Compare Oral PF-06651600, PF-06700841 and Placebo in Subjects With Moderate to Severe Ulcerative Colitis Phase 2 Interventional Pfizer 5