Pruritus is defined as an unpleasant sensation that triggers an itch, namely a desire to scratch. Itch, like pain, is one of the body's basic defense mechanisms. A fundamental biologic function of itch is to alert an animal to the presence of potentially harmful toxins or other hazards such as disease-carrying insects, and to stimulate a reflex aimed at getting rid of these hazards. Itch can manifest acutely, like the reflex to remove fleas and other parasites. Alternatively, chronic itch, like pain, can be become self-perpetuating and pathologic in itself. Chronic itch results when peripheral and central nerves are over-stimulated, which leads to activation and proliferation of pruritus-mediating nerve fibers. Sensitized nerve fibers have been shown to more readily stimulate pruritus. Chronic itch necessitates more than symptomatic treatment, requiring a thorough diagnostic work-up to identify the underlying cause, and multimodal therapy to manage the insidious effects.
Protein kinases are families of enzymes that catalyze the phosphorylation of specific residues in proteins, broadly classified into tyrosine and serine/threonine kinases. Inappropriate kinase activity, arising from mutation, over-expression, or inappropriate regulation, dysregulation, or de-regulation, as well as over- or under-production of growth factors or cytokines has been implicated in many diseases, including but not limited to cancer, cardiovascular diseases, allergies, asthma and other respiratory diseases, autoimmune diseases, inflammatory diseases, bone diseases, metabolic disorders, and neurological and neurodegenerative disorders such as Alzheimer's disease. Inappropriate kinase activity triggers a variety of biological cellular responses relating to cell growth, cell differentiation, survival, apoptosis, mitogenesis, cell cycle control, and cell mobility implicated in the aforementioned and related diseases. Thus, protein kinases have emerged as an important class of enzymes as targets for therapeutic intervention. In particular, the JAK family of cellular protein tyrosine kinases (JAK-1, JAK-2, JAK-3, and Tyk-2) play a central role in cytokine signaling (Kisseleva et al, Gene, 2002, 285, 1; Yamaoka et al. Genome Biology 2004, 5, 253)). Upon binding to their receptors, cytokines activate JAK which then phosphorylate the cytokine receptor, thereby creating docking sites for signaling molecules, notably, members of the signal transducer and activator of transcription (STAT) family that ultimately lead to gene expression, which stimulates biologic responses such as an itch signal. Activation of the JAK-STAT pathway also results in several other ancillary biologic activities that contribute to the inflammation and pruritic processes that contribute to acute allergy in animals but can also exacerbate clinical signs and contribute to chronic allergy.
There are substantial needs for safe and efficacious agents to control atopic dermatitis in animals, including mammals, birds, and fish. Examples of mammals include, but are not limited to, humans, cattle, sheep, goats, llamas, alpacas, pigs, horses, donkeys, dogs, cats, and other livestock or domestic mammals. Examples of birds include turkeys, chickens, ostriches, and other livestock or domestic birds. The market for treating atopic dermatitis in animals is currently dominated by corticosteroids, which cause distressing and undesirable side effects in animals, specifically in companion animals such as dogs. Antihistamines are also used, but are poorly effective. A formulation of cyclosporine (ATOPICA™) is currently being marketed for atopic dermatitis in dogs and cats, but is expensive and has a slow onset of efficacy. In addition, there are GI toleration issues with ATOPICA™. WO 2010/020905 discloses JAK inhibitors for the treatment of pruritus.