Design, Synthesis, and Structure–Activity Relationships of Substituted Phenyl Cyclobutylureas as Potential Modulators of Inflammatory Responses

Background/Objectives: Chronic inflammation underlies many immune-mediated conditions, yet current anti-inflammatory therapies are often limited by incomplete efficacy or safety concerns. Small molecules inspired by soluble epoxide hydrolase (sEH) inhibitors represent a promising scaffold for early-stage exploration. This study describes the design, synthesis, and preliminary biological evaluation of three series of arylurea derivatives (ACBUs) to establish structure–activity relationships and guide chemical optimization. Methods: The compounds were assessed for effects on keratinocyte proliferation, human sEH activity, and the expression of selected inflammatory markers using IL-17A/TNF-α-stimulated HaCaT cells, a relevant in vitro model for preliminary anti-inflammatory profiling. Results: A total of 23 novel ACBU derivatives were synthesized and evaluated. Most compounds showed low antiproliferative activity, allowing selection based on cytotoxicity and solubility. Compounds 4b, 10b, and 16b consistently displayed the most favorable profiles in these preliminary assays. Docking studies provided structural rationales supporting the observed trends and guided further optimization within the series. Conclusions: Compound 4b emerged as the most active candidate in preliminary screening, serving as a reference for ongoing SAR studies. These results highlight the potential of the arylurea scaffold for further chemical optimization and demonstrate the value of early-stage biological profiling in guiding our further studies.