Suppressive Effect of Topically Applied CX-659S, a Novel Diaminouracil Derivative, on the Contact Hypersensitivity Reaction in Various Animal Models

Abstract

Background: The T-cell-mediated contact hypersensitivity reaction (CHR) is thought to be involved in the pathogenesis of clinical cutaneous disorders including atopic dermatitis. A novel diaminouracil derivative, CX-659S, has been reported to have an inhibitory activity against picryl chloride (PC)-induced CHR when administered either orally or percutaneously. The inhibitory effect of topical CX-659S was assessed in three CHR models in the present study. In addition, to elucidate the mechanism of action of this compound, we examined the effect of CX-659S on the expression of messenger RNAs for proinflammatory cytokines after elicitation in PC models. Methods: For the in vivo evaluation of the efficacy of CX-659S, we used PC- or oxazolone-induced CHR in mice and 2,4-dinitrochlorobenzene (DNCB)-induced CHR in guinea pigs. CX-659S was topically applied immediately after the hapten challenge in each model. To assess the effect on gene expression of cytokines, we used the reverse transcriptase-polymerase chain reaction (RT-PCR), a semiquantitative technique with specific primers. Results: Topical CX-659S dose-dependently inhibited ear swelling at 24 h after the challenge in the two mouse models. This inhibitory effect was histologically confirmed in the PC model. Topically applied CX-659S also inhibited erythema and edema formation 24 h after challenge in the guinea pig model. CX-659S inhibited the expression of mRNA for proinflammatory cytokines IL-1β and TNF-α in vivo. Conclusions: Topically applied CX-659S showed significant inhibitory activities against CHR models both in mice and in guinea pigs. Inhibition profiles of CX-659S toward mRNA expression for proinflammatory cytokines corroborated these findings. CX-659S thus could be a useful therapeutic agent for allergic cutaneous disorders such as allergic contact dermatitis and atopic dermatitis.

The Combined Effect of Topical CX-659S, a Novel Diaminouracil Derivative, With Topical Corticosteroid on the Three Types of Allergic Responses in Mice or Guinea Pigs

“…We previously reported that topical CX-659S has an inhibitory activity against typical DTHR; i.e., PC-or OXinduced acute CHR in mice. The inhibitory activities of this compound were also confirmed in guinea pigs with DNCB-induced acute CHR (12). Thus, these unique activities of CX-659S (i.e., this compound exerts inhibitory activity against every ITR, LTR, and DTHR) makes it desirable as a therapeutic agent for AD.…”

“…The inhibitory activities of this compound were also confirmed in guinea pigs with dinitrochlorobenzene (DNCB)-induced acute CHR (12). In addition, this compound profoundly reduced the inflammation responsible for the ear swelling reaction and tissue damages comparable to the intact sample in the murine model of chronic CHR without any other adverse effect such as atrophy, alopecia or telangiectasis observed in mice treated with prednisolone (13).…”

“…This mouse model appears to mimic many, if not all, events occurring within the lesional skin of patients with AD (14 -16). On the other hand, this compound has antioxidative activity toward two reactive oxygen species (hydroxyl radical and peroxynitrite) and toward lipid peroxidation (17) as well as inhibitory activity against pro-inflammatory cytokines and Th-2 type cytokines mRNA expression (12,13).…”

Inhibitory Activities of Novel Pyrimidine Derivatives on the Contact Hypersensitivity Reaction.

“…[2][3][4] This compound, having a tocopherol-related moiety with a non-steroidal structure, exerted a potent radical scavenging activity and inhibitory effects on lipid peroxidation both in vitro and in vivo. 5) Generally, a chiral compound such as CX-659S has many difficulties for the development of it as a new drug candidate. For example, we must establish an efficient, low cost, synthetic method to prepare it, and conduct a comparative study on its pharmacology and toxicology and so on by using each isomer (R or S) and racemate.…”

Synthesis and Activity of a Metabolite of (S)-6-Amino-5-(6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamido)-3-methyl-1-phenyl-2,4-(1H,3H)-pyrimidinedione (CX-659S).

“…1), which showed anti-inflammatory activities against both acute inflammation induced by irritants and delayed-type hypersensitivity in various animal models. [1][2][3] The chemical structure of 1 is quite different from those of typical non-steroidal anti-inflammatory agents, steroid and immunosuppressant, and thus is of interest. In the course of our pharmacokinetic study on 1, a metabolite was commonly observed in the plasma when 1 was administered to animals.…”