ritlecitinib   Click here for help

GtoPdb Ligand ID: 9559

Synonyms: compound 11 [PMID: 28139931] | example 5 [WO2015083028] | Litfulo® | PF-06651600 | PF06651600
Approved drug Immunopharmacology Ligand
ritlecitinib is an approved drug (FDA & UK (2023))
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
SMILES / InChI / InChIKey
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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
InChI Key CBRJPFGIXUFMTM-WDEREUQCSA-N
Immunopharmacology Comments
PF-06651600 is a JAK3 inhibitor with potential clinical utility as a therapeutic option for autoimmune diseases.
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.
Immunopharmacology Disease
Disease X-Refs Comment References
Ulcerative colitis Disease Ontology: DOID:8577
OMIM: 266600
Orphanet: ORPHA771
Phase 2 clinical candidate for UC (NCT02958865).
Crohn's disease Disease Ontology: DOID:8778
OMIM: 266600
Orphanet: ORPHA206
Phase 2 clinical candidate for patients with moderate to severe CD (NCT03395184).
Alopecia areata Disease Ontology: DOID:986
Phase 2b/3 clinical candidate for AA (NCT03732807). In August 2021, Pfizer announced that ritlecitinib had met its primary endpoint (reduction in hair loss) in this study. Results from phase 2a NCT02974868 comparing ritlecitinib and brepocitinib with placebo at 24 weeks were published by King et al. (2021). 2
Rheumatoid arthritis Disease Ontology: DOID:7148
OMIM: 180300
Phase 2 clinical candidate for RA (NCT02969044). In this study oral treatment with ritlecitinib (200 mg once daily) was well tolerated, and was associated with significant improvements in RA disease activit.y 4