3w5e

Publication Abstract from PubMed

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=150nM). 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=7.5nM) and TNF-alpha production in mouse splenocytes (IC50=9.8nM) and showed good in vivo anti-inflammatory activity in the LPS-induced lung inflammation model in mice (ID50=18mg/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.

Identification of the fused bicyclic 4-amino-2-phenylpyrimidine derivatives as novel and potent PDE4 inhibitors.,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 Bioorg Med Chem Lett. 2013 Jun 1;23(11):3325-8. doi: 10.1016/j.bmcl.2013.03.104. , Epub 2013 Apr 4. PMID:23602400^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.