Novartis Institutes for Biomedical Research, Wimblehurst Road, Horsham, West Sussex RH12 5AB, U.K.
J Med Chem. 2012 Sep 13;55(17):7472-9. doi: 10.1021/jm300459a. Epub 2012 Aug 30.
The solubility-driven optimization of a series of 1,7-napthyridine phosphodiesterase-4 inhibitors is described. Directed structural changes resulted in increased aqueous solubility, enabling superior pharmacokinetic properties with retention of PDE4 inhibition. A range of potent and orally bioavailable compounds with good in vivo efficacy in animal models of inflammation and reduced emetic potential compared to previously described drugs were synthesized. Compound 2d was taken forward as a clinical candidate for the treatment of COPD.
描述了一系列 1,7-萘啶磷酸二酯酶-4 抑制剂的溶解度驱动优化。定向结构变化导致水溶解度增加，使 PDE4 抑制作用得以保留，同时具有优越的药代动力学性质。与先前描述的药物相比，合成了一系列具有强大的、口服生物利用度的化合物，在炎症的动物模型中具有良好的体内疗效，并且具有降低的呕吐潜力。化合物 2d 被选为治疗 COPD 的临床候选药物。
