Therapeutic Potential of ASP3258, a Selective Phosphodiesterase 4 Inhibitor, on Chronic Eosinophilic Airway Inflammation

Abstract

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 IC₅₀ 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 IC₅₀ 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 ED₅₀ 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 α₂-adrenoceptor antagonist, repeated administration of ASP3258 (3 mg/kg) had no such inhibitory effect on rats anesthetized with α₂-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.

Absorption, distribution, metabolism and excretion of novel phosphodiesterase type 4 inhibitor ASP3258 in rats

“…ASP3258 (3‐[4‐(3‐chlorophenyl)‐1‐ethyl‐7‐methyl‐2‐oxo‐1,2‐dihydro‐1,8‐naphthyridin‐3‐yl] propanoic acid, Figure ) is a novel PDE4 inhibitor that inhibits PDE4 activity in rat ventricular muscle with an IC 50 of 0.28 nmol/l and exhibits at least 1000 times greater selectivity for PDE4 than PDE1, PDE2, PDE3 or PDE5 . In addition, ASP3258 exhibited anti‐asthma efficacy in two rat models with ED 50 values of 0.81 mg/kg and 0.092 mg/kg . For COPD, ASP3258 (1 mg/kg) showed efficacy as satisfactorily as roflumilast (1 mg/kg) in guinea pigs, whereas glucocorticoid prednisolone did not show any efficacy even at a higher dose (10 mg/kg) .…”

Novel relaxant effects of RPL554 on guinea pig tracheal smooth muscle contractility

“…The relaxation or functional antagonism exerted by PDE3 and PDE4 inhibitors was also dependent on the spasmogenic condition employed but, when the inhibitors were combined, gave a greater inhibitory effect than either inhibitor alone (Turner et al , ; Underwood et al , ; Bernareggi et al , ). The nature of the biphasic response reported with rolipram is unclear, but newer PDE4 inhibitors including roflumilast and cilomilast also produced weak or modest reversal of tone in guinea pig trachea (Bundschuh et al , ; Kobayashi et al , ). The role of PDE4 in airway smooth muscle might be dependent on the spasmogens used to contract tissues.…”

Experimental immunology The activity of phagocytic cells after in vivo administration of propentofylline in mice

“…The most significant inhibitory effects were observed after the use of selective PDE4 inhibitors (i.e. rolipram) [12,14,16,18,[20][21][22]. Gantner et al [16] reported that TNF-α production by monocytes and macrophages is differentially regulated by PDE inhibitors.…”

“…The PDE inhibitors increase the intracellular level of cAMP and/or cGMP and, in consequence, change the activity of many cells, including phagocytic cells. Currently, the PDE4 family is the major target for the drugs affecting the immune system [8,[12][13][14]. Thus, the purpose of this study was to determine the influence of propentofylline, which inhibits principally PDE4, on the activity of phagocytic cells such as peritoneal macrophages and peripheral blood granulocytes and monocytes after in vivo administration in mice.…”