Minimization of drug-drug interaction risk and candidate selection in a natural product-based class of gamma-secretase modulators

被引：5
|
作者：
Hubbs, Jed L. [1 ]
Fuller, Nathan O. [1 ]
Austin, Wesley F. [1 ]
Shen, Ruichao [1 ]
Ma, Jianguo [1 ]
Gong, Zhen [2 ]
Li, Jian [2 ]
Mckee, Timothy D. [1 ]
Loureiro, Robyn M. B. [1 ]
Tate, Barbara [1 ]
Dumin, Jo Ann [1 ]
Ives, Jeffrey [1 ]
Bronk, Brian S. [1 ]
机构：
[1] Satori Pharmaceut Inc, Cambridge, MA 02139 USA
[2] WuXi AppTec Co Ltd, Shanghai 200131, Peoples R China
来源：
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2015年 / 25卷 / 07期
关键词：
Alzheimer's disease; Amyloid-beta; Gamma secretase modulator; Cytochrome P450 3A4; Sterol; Natural product; Semisynthesis; Drug-drug-interactions; OPTIMIZATION;
D O I：
10.1016/j.bmcl.2015.01.051
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
Early lead compounds in this gamma secretase modulator series were found to potently inhibit CYP3A4 and other human CYP isoforms increasing their risk of causing drug-drug-interactions (DDIs). Using structure-activity relationships and CYP3A4 structural information, analogs were developed that minimized this DDI potential. Three of these new analogs were further characterized by rat PK, rat PK/PD and rat exploratory toxicity studies resulting in selection of SPI-1865 (14) as a preclinical development candidate. (C) 2015 Elsevier Ltd. All rights reserved.
引用
收藏
页码：1621 / 1626
页数：6
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