Ritlecitinib (malonate)  (Synonyms: PF-06651600 (malonate))

Ritlecitinib (PF-06651600) malonate is a highly selective, orally active, irreversible covalent JAK3 inhibitor (IC₅₀=33 nM) without inhibitory activity towards JAK1, JAK2, and TYK2 (IC₅₀ >10 μ M). Ritlecitinib malonate rapidly inactivates the JAK3 kinase, and blocks signaling and downstream STAT phosphorylation mediated by common gamma chain cytokines such as IL-2 and IL-15. Ritlecitinib malonate can inhibit Th1/Th17 cell differentiation and function, and effectively suppress preclinical animal models such as alopecia areata, adjuvant-induced arthritis (AIA), and experimental autoimmune encephalomyelitis (EAE)^[1][2][3].

Ritlecitinib malonate inhibits IL-15 in peripheral blood mononuclear cells (PBMCs) and heparin treated human whole blood (HWB) with IC₅₀ of 51 nM and 197 nM, respectively^[1].
Ritlecitinib malonate inhibits the phosphorylation of STAT proteins mediated by IL-2 (STAT5), IL-4 (STAT6), IL-7 (STAT5), IL-15 (STAT5), and IL-21 (STAT3) at concentrations of 244 nM, 340 nM, 407 nM, 266 nM, and 355 nM (IC₅₀), respectively^[2].
Ritlecitinib malonate (30 nM, 167 nM; 5 days, 6 days) inhibits cell differentiation in Th1 and Th17 cell differentiation inhibition experiments for 5 days under Th1 conditions and 6 days under Th17 conditions, respectively^[2].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

Ritlecitinib (3, 10, 30 mg/kg; oral; once daily; 7 days) malonate reduces joint swelling and improves disease severity in a dose-dependent manner in the Sprague-Dawley rat adjuvant-induced arthritis (AIA) model^[2].
Ritlecitinib (30, 100 mg/kg (reversal); 20, 60 mg/kg (prevention); oral; once daily) malonate reduces disease severity in the mouse experimental autoimmune encephalomyelitis (EAE) model^[2].
Ritlecitinib (30 mg/kg; oral; once daily; 4 weeks) malonate can prevent the occurrence of alopecia areata in the C3H/HeJ mouse skin transplantation alopecia areata prevention model; Ritlecitinib (30 mg/kg; oral; once daily; 12 weeks) malonate can reverse the symptoms of alopecia areata, promote hair regeneration and reduce skin inflammation in the C3H/HeJ mouse alopecia areata model^[3].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

389.41

C₁₈H₂₃N₅O₅

2140301-97-7

OC(CC(O)=O)=O.C=CC(N1[C@@H](C)CC[C@@H](NC2=C3C(NC=C3)=NC=N2)C1)=O

Room temperature in continental US; may vary elsewhere.

Please store the product under the recommended conditions in the Certificate of Analysis.

• [1]. Thorarensen A, et al. Design of a Janus Kinase 3 (JAK3) Specific Inhibitor 1-((2 S, 5 R)-5-((7 H-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. Journal of medicinal chemistry, 2017, 60(5): 1971-1993.

  [2]. Telliez JB, et al. Discovery of a JAK3-Selective Inhibitor: Functional Differentiation of JAK3-Selective Inhibition over pan-JAK or JAK1-Selective Inhibition. ACS Chem Biol. 2016 Dec 16;11(12):3442-3451.  [Content Brief]