2. Academic Validation
  3. Discovery of 5-((1H-indazol-3-yl) methylene)-2-thioxoimidazolidin-4-one derivatives as a new class of AHR agonists with anti-psoriasis activity in a mouse model

Discovery of 5-((1H-indazol-3-yl) methylene)-2-thioxoimidazolidin-4-one derivatives as a new class of AHR agonists with anti-psoriasis activity in a mouse model

  • Bioorg Med Chem Lett. 2023 Aug 15;92:129383. doi: 10.1016/j.bmcl.2023.129383.
Guo Zhang 1,  Ziyi Xia 1,  Chenyu Tian 1,  Anjie Xia 2,  Jing You 1,  Jie Liu 1,  Shengyong Yang 1,  Linli Li 3
Affiliations

Affiliations

  • 1 Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 2 Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China; Department of Ophthalmology and Research Laboratory of Macular Disease, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
  • 3 Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, China. Electronic address: [email protected].
PMID: 37348572 DOI: 10.1016/j.bmcl.2023.129383
Abstract

Aryl Hydrocarbon Receptor (AHR) is a ligand dependent transcription factor and participates in the regulation of the immune balance of Th17/22 and Treg cells. It has been found to be widely expressed in the skin, and involved in the pathology of psoriasis. Therefore, AHR is thought as a potential intervention target for psoriasis. Here, we report the discovery of 5-((1H-indazol-3-yl) methylene)-2-thioxoimidazolidin-4-one derivatives as a new class of AHR agonists. Structure-activity relationship analyses led to the identification of the most active compound, 5- ((1H-indazol-3-yl)methylene) -3- (prop-2-yn-1-yl) -2-thiooimidazolidin-4-one (24e), which exhibited an EC50 value of 0.015 µM against AHR. Mechanism of action studies showed that 24e regulated the expression of CYP1A1 by activating the AHR pathway. Topical administration of 24e substantially alleviated imiquimod (IMQ)-induced psoriasis-like skin lesion. Overall, compound 24e could be a good lead compound for drug discovery against psoriasis, and hence deserving further in-depth studies.

Keywords

AHR agonists; Anti-psoriasis; Structure–activity relationship.

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