Synthesis and biological evaluation of 5-carbamoyl-2-phenylpyrimidine derivatives as novel and potent PDE4 inhibitors

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• 作者：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
• 关键词：PDE4 ; PDE4B ; PDE4 inhibitor ; cAMP ; COPD ; Crystallography ; 2-Phenylpyrimidine
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2013
• 出版时间：15 November, 2013
• 年：2013
• 卷：21
• 期：22
• 页码：7025-7037
• 全文大小：2902 K

文摘

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-¦Á) 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.).