Due to the broad anti-inflammatory and immunomodulatory actions of
phosphodiesterase (
PDE) 4 inhibitors, it has been proposed that
PDE4 inhibitors might be efficacious for skin disorders such as
atopic dermatitis.
KF66490 is a newly developed
PDE4 inhibitor that inhibits PDE4B (IC(50)=220 nM) and the production of
tumor necrosis factor (
TNF)-alpha by mouse peritoneal exudated cells stimulated with
lipopolysaccharide (IC(50)=855 nM). To evaluate efficacy of
KF66490 in
atopic dermatitis (AD) models, on skin
inflammation induced by repeated application of
2,4,6-trinitro-1-chlorobenzene (TNCB) on ear in BALB/c mice and on spontaneously AD-like
skin diseases in NC/Nga mice. BALB/c mice were sensitized with 0.3% w/v TNCB applied to the ear on day-7, followed by application three times a week from days 0 to 21. NC/Nga mice spontaneously developed
dermatitis symptoms under conventional conditions. Test compounds were administered orally once daily during experiments. In the TNCB-induced
dermatitis model,
KF66490 significantly inhibited the increase in ear thickness and
interleukin (IL)-4 and IL-1beta levels in the ear. Histopathological and immunohistochemical analysis revealed that
KF66490 significantly inhibited the proliferation of fibroblasts and CD3-positive T cells infiltration into the ear. In addition,
KF66490 significantly suppressed the development of
dermatitis in NC/Nga mice on all observation days, except for 5 and 6 weeks after the first dose. Furthermore,
KF66490 produced less potent
emetic effects than the first generation
PDE4 inhibitor,
rolipram. The present results suggest that
KF66490 has excellent potential as an
oral medicine for the treatment of
atopic dermatitis.