Gallant Michel, Chauret Nathalie, Claveau David, Day Stephen, Deschênes Denis, Dubé Daniel, Huang Zheng, Lacombe Patrick, Laliberté France, Lévesque Jean-François, Liu Susana, Macdonald Dwight, Mancini Joseph, Masson Paul, Mastracchio Anthony, Nicholson Donald, Nicoll-Griffith Deborah A, Perrier Hélène, Salem Myriam, Styhler Angela, Young Robert N, Girard Yves
Merck Frosst Center for Therapeutic Research, Department of Medicinal Chemistry, PO Box 1005, Pointe Claire-Dorval, Que., Canada.
Bioorg Med Chem Lett. 2008 Feb 15;18(4):1407-12. doi: 10.1016/j.bmcl.2008.01.004. Epub 2008 Jan 8.
The structure-activity relationship of a novel series of 8-biarylquinolines acting as type 4 phosphodiesterase (PDE4) inhibitors is described herein. Prototypical compounds from this series are potent and non-selective inhibitors of the four distinct PDE4 (IC(50)<10 nM) isozymes (A-D). In a human whole blood in vitro assay, they inhibit (IC(50)<0.5 microM) the LPS-induced release of the cytokine TNF-alpha. Optimized inhibitors were evaluated in vivo for efficacy in an ovalbumin-induced bronchoconstriction model in conscious guinea pigs. Their propensity to produce an emetic response was evaluated by performing pharmacokinetic studies in squirrel monkeys. This work has led to the identification of several compounds with excellent in vitro and in vivo profiles, including a good therapeutic window of efficacy over emesis.
本文描述了一系列新型8-联芳基喹啉作为4型磷酸二酯酶（PDE4）抑制剂的构效关系。该系列的典型化合物是四种不同PDE4同工酶（A-D）的强效和非选择性抑制剂（IC(50)<10 nM）。在一项人体全血体外试验中，它们抑制（IC(50)<0.5 microM）脂多糖诱导的细胞因子肿瘤坏死因子-α的释放。在清醒豚鼠的卵清蛋白诱导支气管收缩模型中对优化后的抑制剂进行了体内疗效评估。通过在松鼠猴身上进行药代动力学研究评估了它们产生催吐反应的倾向。这项工作已鉴定出几种具有优异体外和体内特性的化合物，包括疗效相对于呕吐有良好的治疗窗。
