Pettersson Martin, Johnson Douglas S, Rankic Danica A, Kauffman Gregory W, Am Ende Christopher W, Butler Todd W, Boscoe Brian, Evrard Edelweiss, Helal Christopher J, Humphrey John M, Stepan Antonia F, Stiff Cory M, Yang Eddie, Xie Longfei, Bales Kelly R, Hajos-Korcsok Eva, Jenkinson Stephen, Pettersen Betty, Pustilnik Leslie R, Ramirez David S, Steyn Stefanus J, Wood Kathleen M, Verhoest Patrick R
Neuroscience and Pain Medicinal Chemistry , Cambridge , Massachusetts 02139 , USA . Email:
Neuroscience and Pain Medicinal Chemistry , Groton , Connecticut 06340 , USA . Email:
Medchemcomm. 2016 Nov 2;8(4):730-743. doi: 10.1039/c6md00406g. eCollection 2017 Apr 1.
Herein we describe the discovery of a novel series of cyclopropyl chromane-derived pyridopyrazine-1,6-dione γ-secretase modulators for the treatment of Alzheimer's disease (AD). Using ligand-based design tactics such as conformational analysis and molecular modeling, a cyclopropyl chromane unit was identified as a suitable heterocyclic replacement for a naphthyl moiety that was present in the preliminary lead . The optimized lead molecule achieved good central exposure resulting in robust and sustained reduction of brain amyloid-β42 (Aβ42) when dosed orally at 10 mg kg in a rat time-course study. Application of the unpaced isolated heart Langendorff model enabled efficient differentiation of compounds with respect to cardiovascular safety, highlighting how minor structural changes can greatly impact the safety profile within a series of compounds.
在此，我们描述了一系列用于治疗阿尔茨海默病（AD）的新型环丙基苯并二氢吡喃衍生的吡啶并吡嗪 -1,6-二酮γ-分泌酶调节剂的发现。利用基于配体的设计策略，如构象分析和分子建模，确定环丙基苯并二氢吡喃单元作为初步先导化合物中存在的萘基部分的合适杂环替代物。在大鼠时间进程研究中，优化后的先导分子口服给药剂量为10 mg/kg时，能实现良好的中枢暴露，从而使脑淀粉样蛋白β42（Aβ42）得到强劲且持续的降低。使用非起搏离体心脏Langendorff模型能够有效区分化合物的心血管安全性，突出了微小结构变化如何对一系列化合物的安全性产生重大影响。
