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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.

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

Goto T,Shiina A,Yoshino T,Mizukami K,Hirahara K,Suzuki O,Sogawa Y,Takahashi T,Mikkaichi T,Nakao N,Takahashi M,Hasegawa M,Sasaki S

doi

10.1016/j.bmcl.2013.03.104

subject

Has Abstract

pub_date

2013-06-01 00:00:00

pages

3325-8

issue

11

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(13)00432-0

journal_volume

23

pub_type

杂志文章

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