Pharmacological Profile of GPD-1116, an Inhibitor of Phosphodiesterase 4

Abstract

We have previously reported that GPD-1116, an inhibitor of phosphodiesterase (PDE) 4, exhibits antiinflammatory effects in a model of cigarette smoke-induced emphysema in senescence-accelerated P1 mice. In the present study, we further characterized the pharmacological profile of GPD-1116 in several experiments in vitro and in vivo. GPD-1116 and its metabolite GPD-1133 predominantly inhibited not only human PDE4, but also human PDE1 in vitro. Moreover, GPD-1116 was effective in several disease models in animals, including acute lung injury, chronic obstructive pulmonary disease (COPD), asthma and pulmonary hypertension; the effective doses of GPD-1116 were estimated to be 0.3-2 mg/kg in these models. With regard to undesirable effects known as class effects of PDE4 inhibitors, GPD-1116 showed suppression of gastric emptying in rats and induction of emesis in dogs, but showed no such suppression of rectal temperature in rats, and these side effects of GPD-1116 seemed to be less potent than those of roflumilast. These results suggested that GPD-1116 could be a promising therapeutic agent for the treatment of inflammatory pulmonary diseases. Furthermore, the inhibitory effects of GPD-1116 for PDE1 might be associated with its excellent pharmacological profile. However, the mechanisms through which PDE1 inhibition contributes to these effects should be determined in future studies. Key words phosphodiesterase; naphthyridine; pulmonary inflammationEnzymes of the cyclic nucleotide phosphodiesterase (PDE) family hydrolyze both cAMP and cGMP. PDE isozymes have been grouped into 11 classes according to their substrate specificity and biochemical features.1) Because inhibition of PDE activity increases intracellular concentrations of cyclic nucleotides by suppressing these degradation to 5′-nucleotides and alters intracellular signal transduction, the PDE family has been recognized as promising targets for therapeutic drugs. For example, inhibitors of PDE3 and PDE5 have actually been used in medicinal therapy for acute heart failure, erectile dysfunction and pulmonary hypertension.1-4) Furthermore, inhibition of PDE4 results in excellent anti-inflammatory effects under experimental conditions, 1,2,5) and an inhibitor of PDE4, roflumilast, has recently emerged as a therapeutic drug for the treatment of chronic obstructive pulmonary disease (COPD). 6)We have previously reported that GPD-1116, a novel PDE4 inhibitor created by ASKA Pharmaceutical, can attenuate the development of cigarette smoke-induced emphysema in senescence-accelerated P1 mice 7) ; however, other pharmacological characteristics of GPD-1116, such as the selectivity toward PDE isozymes and the effects of GPD-1116 in animal models of other pulmonary diseases, have not yet been clarified. In the present study, we clarified more extensive pharmacological profiling of GPD-1116 in several experiments in vitro and in vivo. MATERIALS AND METHODSAnimals Male CD Sprague-Dawley (SD) rats, male Hartley guinea pigs and female Beagle dogs were obtained from Charles Rive...

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