Interleukin-1 (IL-1) is a polypeptide produced mainly by macrophages, which has multiple biological activities including induction of fever, induction of the production of acute phase proteins by hepatocytes, and stimulation of prostaglandins and collagenase production by synovial cells. On the basis of these facts, IL-1 is thought to be an essential mediator of inflammation. In particular, the importance of IL-1 in rheumatoid arthritis (RA) has been reported by various investigators. For example, IL-1 production from RA synovium correlated not only with the degree of inflammation but also with that of joint destruction. Therefore, it is thought that an inhibitor of IL-1 generation could be a useful therapeutic agent in the treatment of RA. From published reports, it is known that some compounds such as SK&F 86002, CP66248, and E5110 reduce IL-1 generation from human monocytes in in vitro studies. In the course of our studies on inhibitors of IL-1 generation using in vitro systems and the rat air-pouch inflammatory model, we have discovered that 3-(5-alkyl-4-hydroxy-3-methoxy-1-naphthalenyl)-2-methyl-2-propenoic acids 3a,b and 5a,b are orally active inhibitors. In particular, (2Z)-3-(5-ethyl-4-hydroxy-3-methoxy-1-naphthalenyl)-2-methyl-2-propenoic acid (5a) was one of the most potent orally active inhibitors of IL-1 generation. In this communication, we describe the synthesis and the pharmacological profile of compound 5a and related compounds.