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

doi:10.1016/j.bmc.2013.09.013

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

Bioorg Med Chem. 2013 Nov 15;21(22):7025-37. doi: 10.1016/j.bmc.2013.09.013. Epub 2013 Sep 19.

Authors

Taiji Goto¹, Akiko Shiina, Toshiharu Yoshino, Kiyoshi Mizukami, Kazuki Hirahara, Osamu Suzuki, Yoshitaka Sogawa, Tomoko Takahashi, Tsuyoshi Mikkaichi, Naoki Nakao, Mizuki Takahashi, Masashi Hasegawa, Shigeki Sasaki

Affiliation

¹ R&D Division, Daiichi Sankyo Co., Ltd, 1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan; Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. Electronic address: goto.taiji.kt@daiichisankyo.co.jp.

PMID: 24094436
DOI: 10.1016/j.bmc.2013.09.013

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.).

Keywords: 2-Phenylpyrimidine; COPD; Crystallography; PDE4; PDE4 inhibitor; PDE4B; cAMP.

MeSH terms

Animals
Anti-Inflammatory Agents / chemical synthesis
Anti-Inflammatory Agents / pharmacology
Anti-Inflammatory Agents / therapeutic use
Binding Sites
Catalytic Domain
Cells, Cultured
Crystallography, X-Ray
Cyclic Nucleotide Phosphodiesterases, Type 4 / chemistry*
Cyclic Nucleotide Phosphodiesterases, Type 4 / metabolism
Enzyme Activation / drug effects
Humans
Lipopolysaccharides / toxicity
Lung Diseases / chemically induced
Lung Diseases / drug therapy
Mice
Phosphodiesterase 4 Inhibitors / chemical synthesis*
Phosphodiesterase 4 Inhibitors / pharmacology*
Phosphodiesterase 4 Inhibitors / therapeutic use
Pyridones / chemical synthesis*
Pyridones / pharmacology*
Pyridones / therapeutic use
Pyrimidines / chemical synthesis*
Pyrimidines / chemistry
Pyrimidines / pharmacology*
Pyrimidines / therapeutic use
Spleen / cytology
Spleen / drug effects
Spleen / metabolism
Tumor Necrosis Factor-alpha / metabolism

Substances

Anti-Inflammatory Agents
Lipopolysaccharides
Phosphodiesterase 4 Inhibitors
Pyridones
Pyrimidines
Tumor Necrosis Factor-alpha
Cyclic Nucleotide Phosphodiesterases, Type 4
pyrimidine