Synthetic Strategy and Evaluation of the Benzyloxy Benzylamide Derivatives as Thymic Stromal Lymphopoietin Modulators for the Treatment of Atopic Dermatitis

Atopic dermatitis (AD) is a chronic inflammatory skin disease driven by immune dysregulation, in which thymic stromal lymphopoietin (TSLP) plays a critical role by triggering type 2 inflammation and exacerbating disease progression. In this study, a screening of our in-house library for inhibition of <i>CCL17</i> mRNA expression led to identification of hit compound <b>6a</b>. Based on this scaffold, benzyloxy benzylamide derivatives were systematically designed and synthesized, followed by the evaluation of their anti-inflammatory potential. Among them, compound <b>14o</b> exhibited the most potent inhibition of <i>CCL17</i> and <i>IL-1B</i> mRNA expression in HaCaT keratinocytes, along with favorable drug-like properties. <b>14o</b> interfered with TSLP receptor dimerization and suppressed the TSLP-induced signal transducer and activator of transcription 5 phosphorylation. Furthermore, <b>14o</b> significantly attenuated TSLP-induced calcium influx and effectively alleviated pruritus and AD-like symptoms in a house dust mite (HDM)-induced AD mouse model. Collectively, these findings highlight <b>14o</b> as a promising topical therapeutic candidate targeting TSLP signaling for the treatment of AD.