Synthesis and biological evaluation of CX-659S and its related compounds for their inhibitory effects on the delayed-type hypersensitivity reaction

In order to find novel nonsteroidal compounds possessing an inhibitory acti vity against delayed-type hypersensitivity (DTH) reactions, we conducted ra ndom screening using a picryl chloride (PC)-induced contact hypersensitivit y reaction (CHR) in mice, and found compound 1 as a lead compound. Then we synthesized and evaluated an extensive series of 5-carboxamidouracil deriva tives focused on both the uracil and the antioxidative moieties. Among them , we found that the hindered phenol moiety was necessary to exhibit the act ivities; especially, compounds 28a 28c having the partial structure of vita min E were found to exert potent activities against the DTH reaction by bot h oral and topical administration. And compound 28c showed antioxidative ac tivity against lipid peroxidation with an IC50 of 5.9 mu M. Compound 28c (C X-659S) was chosen as a candidate drug for the treatment of cutaneous disor ders such as atopic dermatitis and allergic contact dermatitis. (C) 2000 El sevier Science Ltd. All rights reserved.