title: Anti-neutrophilic inflammatory activity of ASP3258, a novel phosphodiesterase type 4 inhibitor.
abstract: Neutrophil-dominant pulmonary inflammation is an important feature of chronic obstructive pulmonary disease (COPD). Here, we evaluated the in vitro and in vivo anti-neutrophilic inflammatory activities of ASP3258, a novel, orally active, and selective phosphodiesterase (PDE) 4 inhibitor with anti-inflammatory potency comparable to that of second-generation compound roflumilast but with lower emetic activity in vivo. In in vitro experiments using human peripheral blood neutrophils, PDE4 inhibitors ASP3258, cilomilast, and roflumilast inhibited fMLP-induced superoxide production in a concentration-dependent manner with IC50 values of 5.0, 96, and 4.7 nM, respectively. ASP3258, cilomilast, and roflumilast also attenuated fMLP-induced neutrophil chemotaxis in a concentration-dependent manner with IC30 values of 18, 270, and 9.7 nM, respectively. In contrast, the glucocorticoid prednisolone inhibited neither superoxide production nor chemotaxis up to 1 μM. In a rat model of lipopolysaccharide (LPS)-induced lung inflammation, orally administered ASP3258, cilomilast, roflumilast, and prednisolone (at 10 or 30 mg/kg) dose-dependently attenuated pulmonary accumulation of neutrophils. The inhibitory effect of ASP3258 was more potent than cilomilast and almost the same as roflumilast and prednisolone. Treatment with ASP3258 inhibited the elevation of TNF-α in the bronchoalveolar lavage fluid following LPS instillation. Histological examination revealed significant inhibition of neutrophil and macrophage infiltration into alveoli by ASP3258. Overall, these findings suggest that ASP3258 has therapeutic potential for treating neutrophilic inflammation such as COPD, partly through direct inhibition of neutrophil activation as well as possibly through inhibition of the TNF-α-mediated pathway.
authors: Pharmacology Research Labs., Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan. satoshi.kubo@jp.astellas.com
authors: Satoshi
authors: S
authors: Kubo
authors: Miki
authors: M
authors: Kobayashi
authors: Masahiro
authors: M
authors: Iwata
authors: Keiji
authors: K
authors: Miyata
authors: Koichiro
authors: K
authors: Takahashi
authors: Yasuaki
authors: Y
authors: Shimizu
mesh_terms: D000328:Adult; D000631:Aminopyridines / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001549:Benzamides / Q000494:pharmacology; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D002478:Cells, Cultured; D054360:Chemokine CXCL1 / Q000276:immunology; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology; D003521:Cyclopropanes / Q000494:pharmacology; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D008070:Lipopolysaccharides; D008297:Male; D009287:Naphthyridines / Q000494:pharmacology / Q000627:therapeutic use*; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology; D009570:Nitriles / Q000494:pharmacology; D058988:Phosphodiesterase 4 Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011014:Pneumonia / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D011239:Prednisolone / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013481:Superoxides / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: C561429:3-(4-(3-chlorophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl)propanoic acid; D000631:Aminopyridines; D000893:Anti-Inflammatory Agents; D001549:Benzamides; D054360:Chemokine CXCL1; C513297:Cxcl1 protein, rat; D003509:Cyclohexanecarboxylic Acids; D003521:Cyclopropanes; D005938:Glucocorticoids; D008070:Lipopolysaccharides; D009287:Naphthyridines; D009570:Nitriles; D058988:Phosphodiesterase 4 Inhibitors; D014409:Tumor Necrosis Factor-alpha; C424423:Roflumilast; D013481:Superoxides; C433247:Cilomilast; D011239:Prednisolone