In order to create novel, topical anti-inflammatory compounds exhibiting more potent activities than lead compound CX-659S (1), we designed and synthesized various derivatives of 1 focusing on the uracil N(1)- and N(3)-substituents, and evaluated their anti-inflammatory activities via inhibition of the picryl chloride-induced contact hypersensitivity reaction (CHR) in mice. In the course of our structure and activity relationship study, we found that compounds 6k, 6q, and 6r inhibited by approximately 50% the CHR, at 0.1 mg/ear. These activities were essentially equipotent with that of Tacrolimus, a strong immunosuppressant.