TS-022, {4-[(1R, 2S, 3R, 5R)-5-Chloro-2-((S)-3-cyclohexyl-3-hydroxyprop-1-ynyl)-3-hydroxycyclopentyl] butylthio}
acetic acid monohydrate, inhibits
ADP-induced platelet aggregation, an effect significantly antagonized, as in the case of
prostaglandin D(2) by the
prostanoid DP(1) receptor antagonist (
BW A868C). TS-022 is a
prostanoid DP(1) receptor agonist, originally developed as a novel anti-pruritic
drug for patients with
atopic dermatitis. We examined the effects of TS-022 on experimental
pruritus, cutaneous barrier disruption, and
atopic dermatitis and in in vitro immune function tests. Topically applied TS-022 significantly suppressed scratching in skin-lesioned NC/Nga mice from a concentration of 2.5 nM, and this scratch-suppressive activity was significantly antagonized by
BW A868C.
Tacrolimus (FK-506) and
dexamethasone, used as reference drugs for
atopic dermatitis, also exhibited suppressive effects against scratching, but only at concentrations of 125 and 25,000 microM. TS-022 applied topically, once a day for 2 days, significantly accelerated repair of the cutaneous barrier disruption caused by mechanical scratching, from concentrations of 2.5 nM. This acceleration of repair of the disrupted cutaneous barrier by this
drug was also significantly antagonized by
BW A868C.
FK-506 and
dexamethasone showed no beneficial effects on the repair of the disrupted cutaneous barrier. Repeated topical application of 2.5 microM of TS-022 and 12.5 microM of
FK-506 once a day for 6 weeks significantly improved the skin
inflammation scores in the NC/Nga mice. In regard to the effects of TS-022 in vitro, the inhibitory activity of TS-022 against
concanavalin A-induced
cytokine production by splenocytes was marginal as compared with that of
FK-506 or
dexamethasone. These results suggest that the beneficial
therapeutic effects of TS-022 in NC/Nga mice with
atopic dermatitis are mediated by its suppressive effect on scratching and its effect of accelerating repair of the disrupted cutaneous barrier, both effects being attributable to its
prostanoid DP(1) receptor agonistic activity.