Evaluation of the Therapeutic Index of a Novel Phosphodiesterase 4B–Selective Inhibitor Over Phosphodiesterase 4D in Mice

Osamu Suzuki; Kiyoshi Mizukami; Maki Etori; Yoshitaka Sogawa; Nana Takagi; Hiroshi Tsuchida; Kiyoshi Morimoto; Taiji Goto; Toshiharu Yoshino; Tsuyoshi Mikkaichi; Kazuki Hirahara; Satoshi Nakamura; Hiroaki Maeda

doi:10.1254/jphs.13103FP

Full Paper

Evaluation of the Therapeutic Index of a Novel Phosphodiesterase 4B–Selective Inhibitor Over Phosphodiesterase 4D in Mice

Osamu Suzuki, Kiyoshi Mizukami, Maki Etori, Yoshitaka Sogawa, Nana Takagi, Hiroshi Tsuchida, Kiyoshi Morimoto, Taiji Goto, Toshiharu Yoshino, Tsuyoshi Mikkaichi, Kazuki Hirahara, Satoshi Nakamura, Hiroaki Maeda

Author information

Osamu Suzuki
Biological Research Laboratories III, Daiichi Sankyo Co., Ltd., Japan
Department of Bioengineering, Tokyo Institute of Technology, Japan
Kiyoshi Mizukami
Biological Research Laboratories III, Daiichi Sankyo Co., Ltd., Japan
Maki Etori
Biological Research Laboratories III, Daiichi Sankyo Co., Ltd., Japan
Yoshitaka Sogawa
Biological Research Laboratories III, Daiichi Sankyo Co., Ltd., Japan
Nana Takagi
Biological Research Laboratories III, Daiichi Sankyo Co., Ltd., Japan
Hiroshi Tsuchida
Biological Research Laboratories III, Daiichi Sankyo Co., Ltd., Japan
Kiyoshi Morimoto
Biological Research Laboratories III, Daiichi Sankyo Co., Ltd., Japan
Taiji Goto
Lead Discovery & Optimization Research Laboratories II, Daiichi Sankyo Co., Ltd., Japan
Toshiharu Yoshino
Lead Discovery & Optimization Research Laboratories II, Daiichi Sankyo Co., Ltd., Japan
Tsuyoshi Mikkaichi
Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd., Japan
Kazuki Hirahara
Biological Research Laboratories III, Daiichi Sankyo Co., Ltd., Japan
Satoshi Nakamura
Department of Bioengineering, Tokyo Institute of Technology, Japan
Hiroaki Maeda
Biological Research Laboratories III, Daiichi Sankyo Co., Ltd., Japan

Keywords: phosphodiesterase 4B (PDE4B), phosphodiesterase 4D (PDE4D), anti-inflammatory effect, gastric adverse effect, therapeutic index

JOURNAL FREE ACCESS

2013 Volume 123 Issue 3 Pages 219-226

DOI https://doi.org/10.1254/jphs.13103FP

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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.

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