Design of Pyridopyrazine-1,6-dione γ-Secretase Modulators that Align Potency, MDR Efflux Ratio, and Metabolic Stability
Design of Pyridopyrazine-1,6-dione γ-Secretase Modulators that Align Potency, MDR Efflux Ratio, and Metabolic Stability
复制标题
DOI：
10.1021/acsmedchemlett.5b00070
复制
发表时间：
2015-05-01
影响因子：
4.2
通讯作者：
Verhoest, Patrick R.
中科院分区：
文献类型：
--
作者：
Pettersson, Martin;Johnson, Douglas S.;Verhoest, Patrick R.
在此，我们描述了一系列用于阿尔茨海默病（AD）的吡啶并吡嗪-1，6-二酮γ-分泌酶调节剂（GSMs）的设计和合成，其实现了良好的效力、代谢稳定性和低MDR流出率的对齐，同时还保持了有利的物理化学性质。具体地说，氟的掺入使得能够设计代谢上不太容易的亲脂性烷基取代基，以增加效力而不损害sp（3）-特征。先导化合物21（PF-06442609）显示出良好的啮齿动物药代动力学特征，在豚鼠时程实验中观察到脑A β 42和A β 40的稳健降低。
Herein we describe the design and synthesis of a series of pyridopyrazine-1,6-dione gamma-secretase modulators (GSMs) for Alzheimer's disease (AD) that achieve good alignment of potency, metabolic stability, and low MDR efflux ratios, while also maintaining favorable physicochemical properties. Specifically, incorporation of fluorine enabled design of metabolically less liable lipophilic alkyl substituents to increase potency without compromising the sp(3)-character. The lead compound 21 (PF-06442609) displayed a favorable rodent pharmacokinetic profile, and robust reductions of brain A beta 42 and A beta 40 were observed in a guinea pig time-course experiment.