title: Identification of the fused bicyclic 4-amino-2-phenylpyrimidine derivatives as novel and potent PDE4 inhibitors.
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.
authors.affiliation: R&D Division, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Tokyo 140-8710, Japan. goto.taiji.kt@daiichisankyo.co.jp
authors.forename: Taiji
authors.initials: T
authors.lastname: Goto
authors.forename: Akiko
authors.initials: A
authors.lastname: Shiina
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Yoshino
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Mizukami
authors.forename: Kazuki
authors.initials: K
authors.lastname: Hirahara
authors.forename: Osamu
authors.initials: O
authors.lastname: Suzuki
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Sogawa
authors.forename: Tomoko
authors.initials: T
authors.lastname: Takahashi
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Mikkaichi
authors.forename: Naoki
authors.initials: N
authors.lastname: Nakao
authors.forename: Mizuki
authors.initials: M
authors.lastname: Takahashi
authors.forename: Masashi
authors.initials: M
authors.lastname: Hasegawa
authors.forename: Shigeki
authors.initials: S
authors.lastname: Sasaki
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D044482:Benzeneacetamides / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D001665:Binding Sites; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000737:chemistry* / Q000378:metabolism; D003499:Cyclic S-Oxides / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D006801:Humans; D008070:Lipopolysaccharides / Q000633:toxicity; D008171:Lung Diseases / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D058988:Phosphodiesterase 4 Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D011485:Protein Binding; D011743:Pyrimidines / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D044482:Benzeneacetamides; D003499:Cyclic S-Oxides; D008070:Lipopolysaccharides; D058988:Phosphodiesterase 4 Inhibitors; D011743:Pyrimidines; D014409:Tumor Necrosis Factor-alpha; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C543000:PDE4B protein, mouse; C030986:pyrimidine