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首页> 外文期刊>Journal of Medicinal Chemistry >Optimization of a Tertiary Alcohol Series of Phosphodiesterase-4 (PDE4) Inhibitors: Structure-Activity Relationship Related to PDE4 Inhibition and Human Ether-a-go-go Related Gene Potassium Channel Binding Affinity
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Optimization of a Tertiary Alcohol Series of Phosphodiesterase-4 (PDE4) Inhibitors: Structure-Activity Relationship Related to PDE4 Inhibition and Human Ether-a-go-go Related Gene Potassium Channel Binding Affinity

机译：磷酸二酯酶-4（PDE4）抑制剂的醇系列的优化：与PDE4抑制和人类以太相关基因钾通道结合亲和力相关的结构-活性关系。

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摘要

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 TNFα 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.
机译：描述了与1相关的磷酸二酯酶4（PDE4）抑制剂的叔醇系列的SAR研究。除了对人全血中PDE4的抑制作用和脂多糖诱导的TNFα的产生外，这些化合物对人类以太相关基因（hERG）钾通道的结合亲和力（一种体外测定评估了导致QTc延长的可能性）。研究了分子中的四个关键结构部分，并评估了所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）被确定为相对于PDE4抑制能力，对hERG钾通道缺乏结合亲和力和药代动力学行为的优化结构。 （+）-3d在几种肺功能模型中表现出良好的体内功效，在呕吐和QTc间隔延长方面具有广泛的治疗指数。

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