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

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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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 (IC 50 = 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.).

Original languageEnglish
Pages (from-to)7025-7037
Number of pages13
JournalBioorganic and Medicinal Chemistry
Volume21
Issue number22
DOIs
Publication statusPublished - Nov 15 2013

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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    Goto, T., Shiina, A., Yoshino, T., Mizukami, K., Hirahara, K., Suzuki, O., Sogawa, Y., Takahashi, T., Mikkaichi, T., Nakao, N., Takahashi, M., Hasegawa, M., & Sasaki, S. (2013). Synthesis and biological evaluation of 5-carbamoyl-2-phenylpyrimidine derivatives as novel and potent PDE4 inhibitors. Bioorganic and Medicinal Chemistry, 21(22), 7025-7037. https://doi.org/10.1016/j.bmc.2013.09.013