Identification of the fused bicyclic 4-amino-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.bmcl.2013.03.104

Identification of the fused bicyclic 4-amino-2-phenylpyrimidine derivatives as novel and potent PDE4 inhibitors

Bioorg Med Chem Lett. 2013 Jun 1;23(11):3325-8. doi: 10.1016/j.bmcl.2013.03.104. Epub 2013 Apr 4.

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, Tokyo 140-8710, Japan. goto.taiji.kt@daiichisankyo.co.jp

PMID: 23602400
DOI: 10.1016/j.bmcl.2013.03.104

Abstract

2-Phenyl-4-piperidinyl-6,7-dihydrothieno[3,4-d]pyrimidine derivative (2) was found to be a new PDE4 inhibitor with moderate PDE4B activity (IC50=150 nM). A number of derivatives with a variety of 4-amino substituents and fused bicyclic pyrimidines were synthesized. Among these, 5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine derivative (18) showed potent PDE4B inhibitory activity (IC50=25 nM). Finally, N-propylacetamide derivative (31b) was determined as a potent inhibitor for both PDE4B (IC50=7.5 nM) and TNF-α production in mouse splenocytes (IC50=9.8 nM) and showed good in vivo anti-inflammatory activity in the LPS-induced lung inflammation model in mice (ID50=18 mg/kg). The binding mode of the new inhibitor (31e) in the catalytic site of PDE4B is presented based on an X-ray crystal structure of the ligand-enzyme complex.

MeSH terms

Animals
Anti-Inflammatory Agents / chemistry*
Anti-Inflammatory Agents / metabolism
Anti-Inflammatory Agents / therapeutic use
Benzeneacetamides / chemistry*
Benzeneacetamides / metabolism
Benzeneacetamides / therapeutic use
Binding Sites
Catalytic Domain
Crystallography, X-Ray
Cyclic Nucleotide Phosphodiesterases, Type 4 / chemistry*
Cyclic Nucleotide Phosphodiesterases, Type 4 / metabolism
Cyclic S-Oxides / chemistry*
Cyclic S-Oxides / metabolism
Cyclic S-Oxides / therapeutic use
Humans
Lipopolysaccharides / toxicity
Lung Diseases / drug therapy
Lung Diseases / pathology
Mice
Phosphodiesterase 4 Inhibitors / chemistry*
Phosphodiesterase 4 Inhibitors / metabolism
Phosphodiesterase 4 Inhibitors / therapeutic use
Protein Binding
Pyrimidines / chemistry*
Pyrimidines / metabolism
Pyrimidines / therapeutic use
Spleen / cytology
Spleen / metabolism
Structure-Activity Relationship
Tumor Necrosis Factor-alpha / metabolism

Substances

Anti-Inflammatory Agents
Benzeneacetamides
Cyclic S-Oxides
Lipopolysaccharides
Phosphodiesterase 4 Inhibitors
Pyrimidines
Tumor Necrosis Factor-alpha
Cyclic Nucleotide Phosphodiesterases, Type 4
PDE4B protein, mouse
pyrimidine