Rational design of a novel template of naphthyridinones rapidly led to PDE4 inhibitors with subnanomolar enzymatic potencies. X-ray crystallography confirmed the binding mode of this novel template. We achieved compounds with double-digit picomolar enzymatic potencies through further structure-based design by targeting both the PDE4 enzyme metal-binding pocket and occupying the solvent-filled pocket. A strategy for lung retention and long duration of action based on low aqueous solubility was followed. In vivo efficacies were measured in a rat lung neutrophilia model by suspension microspray and dry powder administration. Suspension microspray of potent compounds showed in vivo efficacy with a clear dose–response. Despite sustained lung levels, dry powder administration performed much less well and without proper dose–response, highlighting clear differences between the two formulations. This indicates a deficiency in the low aqueous solubility strategy for long duration lung efficacy.

中文翻译：

---

4-氨基-7,8-二氢-1,6-萘啶5（6 H）-作为吸入型磷酸二酯酶4型（PDE4）抑制剂：结构生物学和结构-活性关系

新颖的萘啶酮模板的合理设计迅速导致了具有亚纳摩尔酶活性的PDE4抑制剂。X射线晶体学证实了这种新型模板的结合模式。通过针对PDE4酶金属结合袋并占据溶剂填充袋，通过进一步的基于结构的设计，我们获得了具有两位数皮摩尔酶活性的化合物。遵循了基于低水溶性的保留肺和延长作用时间的策略。通过悬浮微喷雾和干粉给药在大鼠肺嗜中性粒细胞模型中测量了体内功效。悬浮微喷雾显示了体内的有效化合物具有明确的剂量反应的疗效。尽管持续保持肺水平，但干粉给药的效果要差得多，并且没有适当的剂量反应，突出了两种制剂之间的明显差异。这表明对于长期肺功效而言，低水溶性策略缺乏。