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

页码：1621 / 1626

页数：6

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