title: 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 anti-inflammatory 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.
authors.affiliation: Pharmacological Research Department, ASKA Pharmaceutical Co., Ltd.
authors.forename: Takashi
authors.initials: T
authors.lastname: Nose
authors.forename: Miwa
authors.initials: M
authors.lastname: Kondo
authors.forename: Masashi
authors.initials: M
authors.lastname: Shimizu
authors.forename: Hiroki
authors.initials: H
authors.lastname: Hamura
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Yamaguchi
authors.forename: Takako
authors.initials: T
authors.lastname: Sekine
authors.forename: Kouki
authors.initials: K
authors.lastname: Ishitani
mesh_terms: D055371:Acute Lung Injury / Q000188:drug therapy / Q000276:immunology; D000818:Animals; D000941:Antigens; D001249:Asthma / Q000188:drug therapy / Q000276:immunology; D000242:Cyclic AMP / Q000378:metabolism; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism; D004285:Dogs; D004802:Eosinophilia / Q000188:drug therapy / Q000276:immunology; D005260:Female; D005746:Gastric Emptying / Q000187:drug effects; D006168:Guinea Pigs; D006976:Hypertension, Pulmonary / Q000188:drug therapy / Q000503:physiopathology; D008070:Lipopolysaccharides; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D009287:Naphthyridines / Q000494:pharmacology* / Q000627:therapeutic use; D010047:Ovalbumin; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy / Q000473:pathology; D017207:Rats, Sprague-Dawley; D012906:Smoke / Q000009:adverse effects; D014839:Vomiting / Q000139:chemically induced
chemical_list: D000941:Antigens; C527262:GPD-1116; D008070:Lipopolysaccharides; D009287:Naphthyridines; D010726:Phosphodiesterase Inhibitors; D012906:Smoke; D010047:Ovalbumin; D000242:Cyclic AMP; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4