HRI plays critical roles in proliferation and maturation of red blood‐cell precursors, responding to cytoplasmic stress and adaptation to hemoglobin disorders. N,N′‐diarylureas are potent activators of the heme‐regulated inhibitor kinase (HRI), an eIF2‐alpha kinase. We hypothesized that other substituted ureas with potentially more favorable activity and physic‐chemical properties would also activate HRI. Initially, we screened a ~2000 member library containing a diverse array of substituted ureas in the surrogate assay for eIF2‐alpha phosphorylation. We identified di‐substituted aryl‐cyclohexylarylurea as an active scaffold. We explored contributions of substituted aryl and cyclohexylaryl groups to the activity of this scaffold by assembly of a focused library and follow‐up synthesis. We tested N‐aryl, N′‐cyclohexylarylureas in the surrogate assay for eIF2‐alpha phosphorylation and cell proliferation assays, demonstrating significantly improved bioactivities. A random group of these compounds was further characterized in secondary assays for activity and specificity. These agents may become leads for the development of potent, non‐toxic, and target specific anti‐cancer agents.