Lacombe Patrick, Chauret Nathalie, Claveau David, Day Stephen, Deschênes Denis, Dubé Daniel, Gallant Michel, Girard Yves, Huang Zheng, Laliberté France, Lévesque Jean-Francois, Liu Susana, Macdonald Dwight, Mancini Joseph A, Masson Paul, Nicholson Donald W, Nicoll-Griffith Deborah A, Salem Myriam, Styhler Angela, Young Robert N
Merck Frosst Center for Therapeutic Research, Pointe Claire-Dorval, Québec, Canada.
Bioorg Med Chem Lett. 2009 Sep 1;19(17):5266-9. doi: 10.1016/j.bmcl.2009.03.105. Epub 2009 Mar 26.
Substituted 8-arylquinoline analogs bearing alkyl-linked side chain were identified as potent inhibitors of type 4 phophodiesterase. These compounds address the potential liabilities of the clinical candidate L-454560. The pharmacokinetic profile of the best analogs and the in vivo efficacy in an ovalbumin-induced bronchoconstriction assay in conscious guinea pigs are reported.
带有烷基连接侧链的取代8-芳基喹啉类似物被鉴定为4型磷酸二酯酶的有效抑制剂。这些化合物解决了临床候选药物L-454560的潜在缺陷。报道了最佳类似物的药代动力学特征以及在清醒豚鼠卵清蛋白诱导的支气管收缩试验中的体内疗效。