title: Evaluation of the therapeutic index of a novel phosphodiesterase 4B-selective inhibitor over phosphodiesterase 4D in mice.
abstract: Phosphodiesterase 4 (PDE4) inhibitors have been developed for the treatment of pulmonary inflammatory diseases, but their clinical use was dose-limited by mainly gastric adverse effects. Recent studies suggested PDE4B-selective inhibitors over PDE4D are supposed to display a wider therapeutic index than subtype non-selective PDE4 inhibitors such as roflumilast. Compound A was identified as an orally active PDE4B-selective inhibitor over PDE4D both in humans (80-fold selective) and mice (29-fold selective). In this study, the therapeutic effects of compound A and roflumilast were evaluated on lipopolysaccaride (LPS) injection-induced plasma TNF-α elevation and on LPS inhalation-induced pulmonary neutrophilia in mice. The inhibitory effect on gastric emptying in mice was evaluated as a gastric adverse effect. The therapeutic index for TNF-α production (TI(TNF) = ID50 in gastric emptying / ID50 in LPS injection-induced plasma TNF-α elevation) of compound A was larger than roflumilast (9.0 and 0.2, respectively), whereas the therapeutic index for pulmonary neutrophilia (TI(Neu) = ID50 in gastric emptying / ID50 in LPS inhalation-induced pulmonary neutrophilia) of compound A was comparable to roflumilast (1.0 and 0.5, respectively). In conclusion, the TI(Neu) of compound A was not superior compared to that of roflumilast in spite of its high selectivity for PDE4B over PDE4D in mice.
authors.affiliation: Biological Research Laboratories III, Daiichi Sankyo Co., Ltd., Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Suzuki
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Mizukami
authors.forename: Maki
authors.initials: M
authors.lastname: Etori
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Sogawa
authors.forename: Nana
authors.initials: N
authors.lastname: Takagi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tsuchida
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Morimoto
authors.forename: Taiji
authors.initials: T
authors.lastname: Goto
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Yoshino
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Mikkaichi
authors.forename: Kazuki
authors.initials: K
authors.lastname: Hirahara
authors.forename: Satoshi
authors.initials: S
authors.lastname: Nakamura
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Maeda
mesh_terms: D060433:Administration, Ophthalmic; D000631:Aminopyridines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000818:Animals; D001549:Benzamides / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism*; D003521:Cyclopropanes / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D005746:Gastric Emptying / Q000187:drug effects; D006574:Heterocyclic Compounds, 2-Ring / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D007960:Leukocyte Disorders / Q000139:chemically induced / Q000188:drug therapy*; D008070:Lipopolysaccharides; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D020556:Neutrophil Infiltration; D009504:Neutrophils; D010648:Phenylacetates / Q000009:adverse effects / Q000627:therapeutic use*; D058988:Phosphodiesterase 4 Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D011014:Pneumonia / Q000139:chemically induced / Q000188:drug therapy*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: C000589261:2-(4-((2-(3-fluoro-4-methoxyphenyl)-7,8-dihydro-6H-thiopyrano(3,2-d)pyrimidin-4-yl)amino)phenyl)acetic acid; D000631:Aminopyridines; D001549:Benzamides; D003521:Cyclopropanes; D006574:Heterocyclic Compounds, 2-Ring; D008070:Lipopolysaccharides; D010648:Phenylacetates; D058988:Phosphodiesterase 4 Inhibitors; D014409:Tumor Necrosis Factor-alpha; C424423:Roflumilast; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4