Pfizer Worldwide Research & Development , 610 Main Street, Cambridge, Massachusetts 02139, United States.
J Med Chem. 2014 Feb 13;57(3):1046-62. doi: 10.1021/jm401782h. Epub 2014 Jan 28.
Herein we describe the design and synthesis of a novel series of γ-secretase modulators (GSMs) that incorporates a pyridopiperazine-1,6-dione ring system. To align improved potency with favorable ADME and in vitro safety, we applied prospective physicochemical property-driven design coupled with parallel medicinal chemistry techniques to arrive at a novel series containing a conformationally restricted core. Lead compound 51 exhibited good in vitro potency and ADME, which translated into a favorable in vivo pharmacokinetic profile. Furthermore, robust reduction of brain Aβ42 was observed in guinea pig at 30 mg/kg dosed orally. Through chemical biology efforts involving the design and synthesis of a clickable photoreactive probe, we demonstrated specific labeling of the presenilin N-terminal fragment (PS1-NTF) within the γ-secretase complex, thus gaining insight into the binding site of this series of GSMs.
在这里，我们描述了一系列新型γ-分泌酶调节剂（GSMs）的设计和合成，这些调节剂包含了吡啶并哌嗪-1,6-二酮环系统。为了使提高的活性与良好的 ADME 和体外安全性保持一致，我们应用了预期的物理化学性质驱动的设计，结合平行的药物化学技术，得到了一个包含受限构象的核心的新型系列。先导化合物 51 表现出良好的体外活性和 ADME，这转化为有利的体内药代动力学特征。此外，在 30mg/kg 剂量下口服给药的豚鼠中观察到大脑 Aβ42 的显著减少。通过涉及设计和合成可点击光反应探针的化学生物学努力，我们证明了在 γ-分泌酶复合物内特异性标记早老素 N 端片段（PS1-NTF），从而深入了解了这一系列 GSMs 的结合位点。
