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

<b>Background/Objectives</b>: 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. <b>Methods</b>: 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. <b>Results</b>: 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 <b>4b</b>, <b>10b</b>, and <b>16b</b> 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. <b>Conclusions:</b> Compound <b>4b</b> 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.