期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 15, 期 23, 页码 5241-5246出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2005.08.036
关键词
PDE4; TNF-alpha; c-AMP; asthma; COPD
The discovery and SAR of a new series of substituted 8-arylquinoline PDE4 inhibitors are herein described. This work has led to the identification of several compounds with excellent in vitro and in vivo profiles, including a good therapeutic window of emesis to efficacy in several animal models. Typical optimized compounds from this series are potent inhibitors of PDE4 (IC50 < 1 nM) and also of LPS-induced TNF-alpha release in human whole blood (IC50 < 0.5 mu M). The same compounds are potent inhibitors of ovalbumin-induced bronchoconstriction in conscious guinea pigs (EC50 < 0.1 mg/kg ip) but require a dose of about 10 mg/kg po in the squirrel monkey to produce an emetic response. From this series of compounds, 23a (L-454,560) was identified as an optimized compound. (c) 2005 Elsevier Ltd. All rights reserved.
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