Synthesis and biological evaluation of 5-carbamoyl-2-phenylpyrimidine derivatives as novel and potent PDE4 inhibitors |
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| Authors: | Taiji Goto Akiko Shiina Toshiharu Yoshino Kiyoshi Mizukami Kazuki Hirahara Osamu Suzuki Yoshitaka Sogawa Tomoko Takahashi Tsuyoshi Mikkaichi Naoki Nakao Mizuki Takahashi Masashi Hasegawa Shigeki Sasaki |
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| Affiliation: | 1. R&D Division, Daiichi Sankyo Co., Ltd, 1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan;2. Quality & Safety Management Division, Daiichi Sankyo Co., Ltd, 3-5-1, Nihonbashihoncho, Chuo-ku, Tokyo 103-8426, Japan;3. Corporate Strategy Division, Daiichi Sankyo Co., Ltd, 3-5-1, Nihonbashihoncho, Chuo-ku, Tokyo 103-8426, Japan;4. Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan |
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| Abstract: | 5-Carbamoyl-2-phenylpyrimidine derivative 2 has been identified as a phosphodiesterase 4 (PDE4) inhibitor with moderate PDE4B inhibitory activity (IC50 = 200 nM). Modification of the carboxylic acid moiety of 2 gave N-neopentylacetamide derivative 10f, which had high in vitro PDE4B inhibitory activity (IC50 = 8.3 nM) and in vivo efficacy against lipopolysaccharide (LPS)-induced pulmonary neutrophilia in mice (ID50 = 16 mg/kg, ip). Furthermore, based on the X-ray crystallography of 10f bound to the human PDE4B catalytic domain, we designed 7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one derivative 39 which has a fused bicyclic lactam scaffold. Compound 39 exhibited excellent inhibitory activity against LPS-induced tumor necrosis factor alpha (TNF-α) production in mouse splenocytes (IC50 = 0.21 nM) and in vivo anti-inflammatory activity against LPS-induced pulmonary neutrophilia in mice (41% inhibition at a dose of 1.0 mg/kg, i.t.). |
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| Keywords: | PDE4 PDE4B PDE4 inhibitor cAMP COPD Crystallography 2-Phenylpyrimidine |
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