Clinical utility of
phosphodiesterase 4 (
PDE4) inhibitors as
anti-inflammatory agents has, to date, been limited by adverse effects including
nausea and
emesis, making accurate assessment of
emetic versus anti-inflammatory potencies critical to the development of inhibitors with improved therapeutic indices. In the present study we determined the in vitro and in vivo anti-inflammatory potencies of the first-generation
PDE4 inhibitor,
rolipram, the second-generation inhibitors,
roflumilast and
cilomilast, and a novel third generation inhibitor, 1-ethyl-5-{5-[(4-methyl-1-piperazinyl)methyl]-1,3,4-oxadiazol-2-yl}-N-(tetrahydro-2H-
pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-
amine (EPPA-1). The rank-order potency against
lipopolysaccharide (LPS)-induced
tumor necrosis factor-alpha production by human peripheral blood mononuclear cells was
roflumilast (IC(50) = 5 nM) >
EPPA-1 (38) >
rolipram (269) >
cilomilast (389), and against LPS-induced pulmonary neutrophilia in the rat was
EPPA-1 (D(50) = 0.042 mg/kg) >
roflumilast (0.24) >
rolipram (3.34) >
cilomilast (4.54).
Pica, the consumption of non-nutritive substances in response to gastrointestinal stress, was used as a surrogate measure for
emesis, giving a rank-order potency of
rolipram (D(50) = 0.495 mg/kg) >
roflumilast (1.6) >
cilomilast (6.4) >
EPPA-1 (24.3). The low and high emetogenic activities of
EPPA-1 and
rolipram, respectively, detected in the
pica model were confirmed in a second surrogate model of
emesis, reversal of alpha(2)-adrenoceptor-mediated
anesthesia in the mouse. The rank order of therapeutic indices derived in the rat [(
pica D(50))/(neutrophilia D(50))] was
EPPA-1 (578) >
roflumilast (6.4) >
cilomilast (1.4) >
rolipram (0.15), consistent with the rank order derived in the ferret [(
emesis D(50))/(neutrophilia D(50))]. These data validate rat
pica feeding as a surrogate for
PDE4 inhibitor-induced
emesis in higher species, and identify
EPPA-1 as a novel
PDE4 inhibitor with an improved therapeutic index.