Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 21, Issue 22, Pages 7025-7037Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2013.09.013
Keywords
PDE4; PDE4B; PDE4 inhibitor; cAMP; COPD; Crystallography; 2-Phenylpyrimidine
Funding
- Grants-in-Aid for Scientific Research [21229002] Funding Source: KAKEN
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5-Carbamoyl-2-phenylpyrimidine derivative 2 has been identified as a phosphodiesterase 4 (PDE4) inhibitor with moderate PDE4B inhibitory activity (IC50 = 200 nM). Modification of the carboxylic acid moiety of 2 gave N-neopentylacetamide derivative 10f, which had high in vitro PDE4B inhibitory activity (IC50 = 8.3 nM) and in vivo efficacy against lipopolysaccharide (LPS)-induced pulmonary neutrophilia in mice (ID50 = 16 mg/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 = 0.21 nM) and in vivo anti-inflammatory activity against LPS-induced pulmonary neutrophilia in mice (41% inhibition at a dose of 1.0 mg/kg, i.t.). (C) 2013 Elsevier Ltd. All rights reserved.
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