We investigated and compared the pharmacological effects of a
PDE4 inhibitor ASP3258 (3-[4-(3-chlorophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl]
propanoic acid), with those of
roflumilast, the most clinically advanced
PDE4 inhibitor known.
ASP3258 inhibited human PDE4A, 4B, 4C, and 4D with respective IC(50) values of 0.036, 0.050, 0.45, and 0.035 nmol/l, all approximately 3-6 times more potent than
roflumilast.
ASP3258 inhibited LPS-induced TNF-α production and PHA-induced
IL-5 production in human whole blood cells with respective IC(50) values of 110 and 100 nmol/l, both approximately 10 times less potent than
roflumilast. Repeatedly administered
ASP3258 and
roflumilast both suppressed chronic airway
eosinophilia induced by repeated exposure to
ovalbumin in Brown Norway rats with respective ED(50) values of 0.092 and 0.17 mg/kg. We also evaluated the toxicological profiles of
ASP3258. Although
PDE4 inhibitors induce
emesis by mimicking the pharmacological action of an α(2)-adrenoceptor antagonist, repeated administration of
ASP3258 (3 mg/kg) had no such inhibitory effect on rats anesthetized with α(2) -
adrenoceptor agonist.
PDE4 inhibitors are also known to induce
vascular injury in rats. Although repeatedly administered
ASP3258 (3 and 10 mg/kg) significantly increased plasma
fibrinogen, a
biomarker for toxicity, 1 mg/kg of
ASP3258 did not. These results suggest that
ASP3258 is an attractive
PDE4 inhibitor for treating chronic eosinophilic airway
inflammation due to
asthma.