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

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.
Taiji Goto 1,  Akiko Shiina,  Toshiharu Yoshino,  Kiyoshi Mizukami,  Kazuki Hirahara,  Osamu Suzuki,  Yoshitaka Sogawa,  Tomoko Takahashi,  Tsuyoshi Mikkaichi,  Naoki Nakao,  Mizuki Takahashi,  Masashi Hasegawa,  Shigeki Sasaki
Affiliations

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.

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