3wd9

Publication Abstract from PubMed

5-Carbamoyl-2-phenylpyrimidine derivative 2 has been identified as a phosphodiesterase 4 (PDE4) inhibitor with moderate PDE4B inhibitory activity (IC50=200nM). Modification of the carboxylic acid moiety of 2 gave N-neopentylacetamide derivative 10f, which had high in vitro PDE4B inhibitory activity (IC50=8.3nM) and in vivo efficacy against lipopolysaccharide (LPS)-induced pulmonary neutrophilia in mice (ID50=16mg/kg, ip). Furthermore, based on the X-ray crystallography of 10f bound to the human PDE4B catalytic domain, we designed 7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one derivative 39 which has a fused bicyclic lactam scaffold. Compound 39 exhibited excellent inhibitory activity against LPS-induced tumor necrosis factor alpha (TNF-alpha) production in mouse splenocytes (IC50=0.21nM) and in vivo anti-inflammatory activity against LPS-induced pulmonary neutrophilia in mice (41% inhibition at a dose of 1.0mg/kg, i.t.).

Synthesis and biological evaluation of 5-carbamoyl-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. 2013 Nov 15;21(22):7025-37. doi: 10.1016/j.bmc.2013.09.013. Epub, 2013 Sep 19. PMID:24094436^[3]

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