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

Abstract

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 ofmRNA expression led to identification of hit compound. Based on this scaffold, benzyloxy benzylamide derivatives were systematically designed and synthesized, followed by the evaluation of their anti-inflammatory potential. Among them, compoundexhibited the most potent inhibition ofandmRNA expression in HaCaT keratinocytes, along with favorable drug-like properties.interfered with TSLP receptor dimerization and suppressed the TSLP-induced signal transducer and activator of transcription 5 phosphorylation. Furthermore,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 highlightas a promising topical therapeutic candidate targeting TSLP signaling for the treatment of AD.