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 & EMA (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
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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
1. Brown MF, Casimiro-Garcia A, Che Y, Coe JW, Flanagen ME, Gilbert AM, Hayward MM, Langille JD, Montgomery JI, Telliez J-B et al.. (2015)
Pyrrolo[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyrazinyl and pyrrolo[2,3-d]pyridinyl acrylamides.
Patent number: WO2015083028. Assignee: Pfizer Inc.. Priority date: 05/12/2013. Publication date: 11/06/2015.
2. King B, Guttman-Yassky E, Peeva E, Banerjee A, Sinclair R, Pavel AB, Zhu L, Cox LA, Craiglow B, Chen L et al.. (2021)
A phase 2a randomized, placebo-controlled study to evaluate the efficacy and safety of the oral Janus kinase inhibitors ritlecitinib and brepocitinib in alopecia areata: 24-week results.
J Am Acad Dermatol, 85 (2): 379-387. [PMID:33757798]
3. King B, Zhang X, Harcha WG, Szepietowski JC, Shapiro J, Lynde C, Mesinkovska NA, Zwillich SH, Napatalung L, Wajsbrot D et al.. (2023)
Efficacy and safety of ritlecitinib in adults and adolescents with alopecia areata: a randomised, double-blind, multicentre, phase 2b-3 trial.
Lancet, 401 (10387): 1518-1529. [PMID:37062298]
4. Robinson MF, Damjanov N, Stamenkovic B, Radunovic G, Kivitz A, Cox L, Manukyan Z, Banfield C, Saunders M, Chandra D et al.. (2020)
Efficacy and Safety of PF-06651600 (Ritlecitinib), a Novel JAK3/TEC Inhibitor, in Patients With Moderate-to-Severe Rheumatoid Arthritis and an Inadequate Response to Methotrexate.
Arthritis Rheumatol, 72 (10): 1621-1631. [PMID:32419304]
5. Sandborn WJ, Danese S, Leszczyszyn J, Romatowski J, Altintas E, Peeva E, Hassan-Zahraee M, Vincent MS, Reddy PS, Banfield C et al.. (2023)
Oral Ritlecitinib and Brepocitinib for Moderate-to-Severe Ulcerative Colitis: Results From a Randomized, Phase 2b Study.
Clin Gastroenterol Hepatol, 21 (10): 2616-2628.e7. [PMID:36623678]
6. Telliez JB, Dowty ME, Wang L, Jussif J, Lin T, Li L, Moy E, Balbo P, Li W, Zhao Y et al.. (2016)
Discovery of a JAK3-Selective Inhibitor: Functional Differentiation of JAK3-Selective Inhibition over pan-JAK or JAK1-Selective Inhibition.
ACS Chem Biol, 11 (12): 3442-3451. [PMID:27791347]
7. Thorarensen A, Dowty ME, Banker ME, Juba B, Jussif J, Lin T, Vincent F, Czerwinski RM, Casimiro-Garcia A, Unwalla R et al.. (2017)
Design of a Janus Kinase 3 (JAK3) Specific Inhibitor 1-((2S,5R)-5-((7H-Pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one (PF-06651600) Allowing for the Interrogation of JAK3 Signaling in Humans.
J Med Chem, 60 (5): 1971-1993. [PMID:28139931]