Friesen Richard W, Ducharme Yves, Ball Richard G, Blouin Marc, Boulet Louise, Côté Bernard, Frenette Richard, Girard Mario, Guay Daniel, Huang Zheng, Jones Thomas R, Laliberté France, Lynch Joseph J, Mancini Joseph, Martins Evelyn, Masson Paul, Muise Eric, Pon Douglas J, Siegl Peter K S, Styhler Angela, Tsou Nancy N, Turner Mervyn J, Young Robert N, Girard Yves
Department of Biology and Medicinal Chemistry, Merck Frosst Centre for Therapeutic Research, P.O. Box 1005, Pointe Claire-Dorval, Quebec, H9R 4P8, Canada.
J Med Chem. 2003 Jun 5;46(12):2413-26. doi: 10.1021/jm0204542.
A SAR study on the tertiary alcohol series of phosphodiesterase-4 (PDE4) inhibitors related to 1 is described. In addition to inhibitory potency against PDE4 and the lipopolysaccharide-induced production of TNFalpha in human whole blood, the binding affinity of these compounds for the human ether-a-go-go related gene (hERG) potassium channel (an in vitro measure for the potential to cause QTc prolongation) was assessed. Four key structural moieties in the molecule were studied, and the impact of the resulting modifications in modulating these activities was evaluated. From these studies, (+)-3d (L-869,298) was identified as an optimized structure with respect to PDE4 inhibitory potency, lack of binding affinity to the hERG potassium channel, and pharmacokinetic behavior. (+)-3d exhibited good in vivo efficacy in several models of pulmonary function with a wide therapeutic index with respect to emesis and prolongation of the QTc interval.
描述了对与1相关的磷酸二酯酶-4（PDE4）抑制剂叔醇系列的构效关系研究。除了对PDE4的抑制效力以及脂多糖诱导的人全血中肿瘤坏死因子α的产生外，还评估了这些化合物对人醚-去极化相关基因（hERG）钾通道的结合亲和力（一种体外测量导致QTc延长可能性的方法）。研究了分子中的四个关键结构部分，并评估了由此产生的修饰对调节这些活性的影响。从这些研究中，（+）-3d（L-869,298）被确定为在PDE4抑制效力、对hERG钾通道缺乏结合亲和力以及药代动力学行为方面的优化结构。（+）-3d在几种肺功能模型中表现出良好的体内疗效，在呕吐和QTc间期延长方面具有较宽的治疗指数。
