Discovery of a substituted 8-arylquinoline series of PDE4 inhibitors: Structure–activity relationship, optimization, and identification of a highly potent, well tolerated, PDE4 inhibitor

详细信息	查看全文 | 推荐本文 |

• 作者：Dwight Macdonald ; Anthony Mastracchio ; Hé ; lè ; ne Perrier ; Daniel Dubé ; Michel Gallant ; Patrick Lacombe ; Denis Deschê ; nes ; Bruno Roy ; John Scheigetz ; Kevin Bateman et al.
• 关键词：PDE4 ; TNF-α ; c-AMP ; Asthma ; COPD
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2005
• 期刊代码：10_0960894x
• 类别：ch
• 出版时间：2005
• 卷：15
• 期：23
• 页码：5241-5246
• 文件大小：155 K

摘要

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-α release in human whole blood (IC₅₀ < 0.5 μM). 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.