TY - JOUR
T1 - Identification of the fused bicyclic 4-amino-2-phenylpyrimidine derivatives as novel and potent PDE4 inhibitors
AU - Goto, Taiji
AU - Shiina, Akiko
AU - Yoshino, Toshiharu
AU - Mizukami, Kiyoshi
AU - Hirahara, Kazuki
AU - Suzuki, Osamu
AU - Sogawa, Yoshitaka
AU - Takahashi, Tomoko
AU - Mikkaichi, Tsuyoshi
AU - Nakao, Naoki
AU - Takahashi, Mizuki
AU - Hasegawa, Masashi
AU - Sasaki, Shigeki
N1 - Copyright:
Copyright 2014 Elsevier B.V., All rights reserved.
PY - 2013/6/1
Y1 - 2013/6/1
N2 - 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 (IC 50 = 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.
AB - 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 (IC 50 = 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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U2 - 10.1016/j.bmcl.2013.03.104
DO - 10.1016/j.bmcl.2013.03.104
M3 - Article
C2 - 23602400
AN - SCOPUS:84877582531
VL - 23
SP - 3325
EP - 3328
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
SN - 0960-894X
IS - 11
ER -