delgocitinib and Disease-Models--Animal

Topics: Administration, Cutaneous; Animals; Antipruritics; Dermatitis, Atopic; Disease Models, Animal; Female; Humans; Janus Kinase Inhibitors; Male; Mice; Pruritus; Pyrroles; Skin

To evaluate the pharmacological properties of JTE-052, a novel Janus kinase (JAK) inhibitor.. The JAK inhibitory activity of JTE-052 was evaluated using recombinant human enzymes. The inhibitory effects on cytokine signaling pathways were evaluated using primary human inflammatory cells. The in vivo efficacy and potency of JTE-052 were examined in a mouse interleukin (IL)-2-induced interferon (IFN)-γ production model and a rat collagen-induced arthritis model.. JTE-052 inhibited the JAK1, JAK2, JAK3, and tyrosine kinase (Tyk)2 enzymes in an adenosine triphosphate (ATP)-competitive manner and inhibited cytokine signaling evoked by IL-2, IL-6, IL-23, granulocyte/macrophage colony-stimulating factor, and IFN-α. JTE-052 inhibited the activation of inflammatory cells, such as T cells, B cells, monocytes, and mast cells, in vitro. Oral dosing of JTE-052 resulted in potent suppression of the IL-2-induced IFN-γ production in mice with an ED50 value of 0.24 mg/kg, which was more potent than that of tofacitinib (ED50 = 1.1 mg/kg). In the collagen-induced arthritis model, JTE-052 ameliorated articular inflammation and joint destruction even in therapeutic treatments where methotrexate was ineffective.. The present results indicate that JTE-052 is a highly potent JAK inhibitor, and represents a candidate anti-inflammatory agent for suppressing various types of inflammation.

Topics: Animals; Anti-Inflammatory Agents; Antirheumatic Agents; Arthritis, Experimental; B-Lymphocytes; Cells, Cultured; Collagen; Cytokines; Disease Models, Animal; Humans; In Vitro Techniques; Inflammation; Interferon-gamma; Interleukin-2; Janus Kinases; Mast Cells; Methotrexate; Mice; Mice, Inbred DBA; Protein Kinase Inhibitors; Rats; Rats, Inbred Lew; Signal Transduction; T-Lymphocytes