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

• Published in: Bioorganic & medicinal chemistry letters 2005-12, Vol.15 (23), p.5241-5246
• Main Authors: Macdonald, Dwight, Mastracchio, Anthony, Perrier, Hélène, Dubé, Daniel, Gallant, Michel, Lacombe, Patrick, Deschênes, Denis, Roy, Bruno, Scheigetz, John, Bateman, Kevin, Li, Chun, Trimble, Laird A., Day, Stephen, Chauret, Nathalie, Nicoll-Griffith, Deborah A., Silva, Jose M., Huang, Zheng, Laliberté, France, Liu, Susana, Ethier, Diane, Pon, Doug, Muise, Eric, Boulet, Louise, Chan, Chi Chung, Styhler, Angela, Charleson, Stella, Mancini, Joseph, Masson, Paul, Claveau, David, Nicholson, Donald, Turner, Mervyn, Young, Robert N., Girard, Yves
• Format: Article
• Language: English
• Subjects: 3',5'-Cyclic-AMP Phosphodiesterases - antagonists & inhibitors; Animals; Asthma; Bronchoconstriction - drug effects; c-AMP; COPD; Cyclic Nucleotide Phosphodiesterases, Type 4; Guinea Pigs; Humans; Inhibitory Concentration 50; PDE4; Phosphodiesterase Inhibitors - chemistry; Phosphodiesterase Inhibitors - pharmacology; Phosphodiesterase Inhibitors - toxicity; Quinolines - chemistry; Quinolines - pharmacology; Quinolines - toxicity; Rats; Saimiri; Sheep; Structure-Activity Relationship; TNF-α; Vomiting - chemically induced
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2005.08.036

The discovery and SAR of a new series of substituted 8-arylquinoline PDE4 inhibitors are described. From this series of compounds, the development candidate L-454,560 was selected. 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 (IC 50 < 1 nM) and also of LPS-induced TNF-α release in human whole blood (IC 50 < 0.5 μM). The same compounds are potent inhibitors of ovalbumin-induced bronchoconstriction in conscious guinea pigs (EC 50 < 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.