Discovery of indole-derived pyridopyrazine-1,6-dione γ-secretase modulators that target presenilin
Discovery of indole-derived pyridopyrazine-1,6-dione γ-secretase modulators that target presenilin
复制标题
DOI：
10.1016/j.bmcl.2014.12.059
复制
发表时间：
2015-02-15
影响因子：
2.7
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.
在这里，我们描述的设计策略，导致发现新的吡啶并吡嗪-1，6-二酮γ-分泌酶调节剂（GSMs）纳入吲哚基序作为杂环取代原来的铅9中存在的萘基部分。涉及并行药物化学和原位单体合成制备重点库的策略进行了讨论。优化的吲哚GSM 29表现出良好的体外效力和物理化学性质的一致性，并且当以30 mg/kg口服给药时，在大鼠功效模型中实现了脑A β 42的中度降低。使用可点击的吲哚衍生的GSM光亲和探针的标记实验表明，该系列结合到γ-分泌酶复合物的早老素N-末端片段（PS1-NTF）。(C)2014爱思唯尔有限公司版权所有。
Herein we describe design strategies that led to the discovery of novel pyridopyrazine-1,6-dione gamma-secretase modulators (GSMs) incorporating an indole motif as a heterocyclic replacement for a naphthyl moiety that was present in the original lead 9. Tactics involving parallel medicinal chemistry and in situ monomer synthesis to prepare focused libraries are discussed. Optimized indole GSM 29 exhibited good alignment of in vitro potency and physicochemical properties, and moderate reduction of brain A beta 42 was achieved in a rat efficacy model when dosed orally at 30 mg/kg. Labeling experiments using a clickable, indole-derived GSM photoaffinity probe demonstrated that this series binds to the presenilin N-terminal fragment (PS1-NTF) of the gamma-secretase complex. (C) 2014 Elsevier Ltd. All rights reserved.