Dual Inhibition of IL-2-Inducible T‑Cell Kinase (ITK) and Tropomyosin Receptor Kinase A (TRKA) as Potential Treatment for Atopic Dermatitis and Other Inflammatory and Autoimmune Diseases Ahmed F. Abdel-Magid* Cite This: https://doi.org/10.1021/acsmedchemlett.1c00619 Read Online ACCESS Metrics & More Article Recommendations Important Compound Classes. Title. Benzimidazole Derivatives Patent Publication Number. WO 2021/124155 A1 Publication Date. June 24, 2021 Priority Applications. US 62/951,030 and US 63/108,602 Priority Dates. December 20, 2019 and November 2, 2020 Inventors. Bagley, S. W.; Casimiro-Garcia, A.; Cheng, X.; Davoren, J. E.; Denny, R. A.; Gerstenberger, B. S.; Lovering, F. E.; Parikh, M. D.; Strohbach, J. W.; Trujillo, J. I. Assignee Company. Pfizer, Inc.; 235 East 42nd Street, New York, New York 10017, USA Disease Area. Inflammatory and autoimmune diseases such as atopic dermatitis Biological Target. Interleukin-2-inducible T-cell kinase (ITK) and tropomyosin receptor kinase A (TRKA). Summary. The invention in this patent application relates to benzimidazole derivatives generally represented by formula 1. These compounds are inhibitors of ITK and may be useful as a treatment of inflammatory and autoimmune diseases including skin diseases such as atopic dermatitis. These compounds are also inhibitors of TRKA, and thus they may potentially provide more effective treatment for these diseases. Atopic dermatitis (AD), the most common form of eczema, is a chronic inflammatory skin disease that can affect both children and adults; however, most cases start at childhood. AD patients usually suffer from inflamed, red, cracked, and dry skin. They may also develop unpleasant pruritic skin lesions that cause intense scratching and impair their quality of life. Genetic and environmental factors are possible contributors to skin barrier disruption and immune hyperactivation, which are key drivers of AD pathogenesis. Dupilumab (also known as Dupixent), is a monoclonal antibody that was approved by the FDA in 2017 to treat moderate to severe atopic dermatitis. The clinical development of this drug has revealed a pathogenic role for T cells and the T- helper 2 (Th2) cell-derived cytokines, IL-4 and IL-13, in AD. Other studies have determined that Th1 cells, Th22 cells, and Th17 cells as well as the cytokines produced by them, IFN-γ, IL- 22, and IL-17, respectively, contribute to the pathogenesis of AD. The cytokine activities observed in these studies are consistent with those observed in the early clinical studies of Janus kinase (JAK) inhibitors. JAK inhibitors function by blocking the signaling of IL-4, IL-13, and other inflammatory cytokines produced in the skin. These findings have presented researchers with a potential alternative therapeutic strategy to effectively modulate this pathway through controlling the production of IL-4 and IL-13. They also suggest that targeting the modulation of the predominant T-cell-driven inflammatory response would possibly be an effective anti-inflammatory therapy for the treatment of AD. ITK is a member of the Tec family of nonreceptor protein tyrosine kinases (TFKs). ITK is highly expressed in immune cells such as T, natural killer (NK), natural killer T (NKT), and mast cells. ITK is essential for proximal T-cell receptor (TCR) signaling. It amplifies TCR-dependent signals to promote T-cell activation, cytokine production, and T-cell proliferation. Elevated levels of ITK were observed in the peripheral T cells and skin lesions of patients with moderate to severe AD. The inhibition of ITK activity in T cells suppresses the TCR-induced production of cytokines IL-4 and IL-13 and may thus be a useful therapeutic target in the treatment of AD. ITK also contributes to the production of other TCR-dependent pro-inflammatory cytokines such as IL-2, IL-17, IL-22, IL-31, IFNy, and TNF-α; therefore, its inhibition is expected to display increased efficacy Received: November 3, 2021 Patent Highlight pubs.acs.org/acsmedchemlett Published XXXX by American Chemical Society A https://doi.org/10.1021/acsmedchemlett.1c00619 ACS Med. Chem. Lett. XXXX, XXX, XXX-XXX Downloaded via 54.227.5.27 on November 21, 2021 at 11:56:25 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.