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

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

  • J Med Chem. 2025 Dec 30. doi: 10.1021/acs.jmedchem.5c02461.
Kyoung Hee Seo 1 2 3,  Bo Ko Jang 1 2 3,  Seul Ki Yeon 1,  Hyeon Ji Kim 1,  Ye Rim Lee 1,  Ran Seo 3,  Wok-Joo Lee 4,  Yoowon Kim 1,  Elijah Hwejin Lee 1 2,  Dong-Gi Lee 3,  Han-Seung Lee 3,  Jong-Hyun Park 1,  Won-Sik Shim 4,  Jong-Seung Lee 3,  Ji Won Choi 1,  Ki Duk Park 1 2
Affiliations

Affiliations

  • 1 Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea.
  • 2 Division of Bio-Medical Science & Technology, KIST School, University of Science and Technology (UST), Seoul 02792, Republic of Korea.
  • 3 AmtixBio Co., Ltd., Hanam-si, Gyeonggi-do 12925, Republic of Korea.
  • 4 College of Pharmacy, Gachon University, Hambangmoe-ro 191, Yeonsu-gu, Incheon 21936, Republic of Korea.
PMID: 41467342 DOI: 10.1021/acs.jmedchem.5c02461
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 of CCL17 mRNA expression led to identification of hit compound 6a. Based on this scaffold, benzyloxy benzylamide derivatives were systematically designed and synthesized, followed by the evaluation of their anti-inflammatory potential. Among them, compound 14o exhibited the most potent inhibition of CCL17 and IL-1B mRNA expression in HaCaT keratinocytes, along with favorable drug-like properties. 14o interfered with TSLP receptor dimerization and suppressed the TSLP-induced signal transducer and activator of transcription 5 phosphorylation. Furthermore, 14o 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 14o as a promising topical therapeutic candidate targeting TSLP signaling for the treatment of AD.

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