Journal of medicinal chemistry · 2023
Discovery of the Potent and Selective Inhaled Janus Kinase 1 Inhibitor AZD4604 and Its Preclinical Characterization.
СтатьяНазвание и аннотация: Перевод в очереди
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Nilsson Magnus, Berggren Kristina, Berglund Susanne, Cerboni Silvia, Collins Mia, Dahl Göran, Elmqvist David, Grimster Neil P, Hendrickx Ramon, Johansson Johan R, Kettle Jason G, Lepistö Matti, Rhedin Magdalena, Smailagic Amir, Su Qibin, Wennberg Tiiu, Wu Allan, Österlund Torben, Naessens Thomas, Mitra Suman
Аннотация
JAK-STAT cytokines are critical in regulating immunity. Persistent activation of JAK-STAT signaling pathways by cytokines drives chronic inflammatory diseases such as asthma. Herein, we report on the discovery of a highly JAK1-selective, ATP-competitive series of inhibitors having a 1000-fold selectivity over other JAK family members and the approach used to identify compounds suitable for inhaled administration. Ultimately, compound 16 was selected as the clinical candidate, and upon dry powder inhalation, we could demonstrate a high local concentration in the lung as well as low plasma concentrations, suggesting no systemic JAK1 target engagement. Compound 16 has progressed into clinical trials. Using 16, we found JAK1 inhibition to be more efficacious than JAK3 inhibition in IL-4-driven Th2 asthma.