Preparation and biological evaluation of conformationally constrained BACE1 inhibitors

被引：15

作者：

Winneroski, Leonard L. ^{[1
]}

Schiffler, Matthew A. ^{[1
]}

Erickson, Jon A. ^{[1
]}

May, Patrick C. ^{[1
]}

Monk, Scott A. ^{[1
]}

Timm, David E. ^{[1
]}

Audia, James E. ^{[1
]}

Beck, James P. ^{[1
]}

Boggs, Leonard N. ^{[1
]}

Borders, Anthony R. ^{[1
]}

Boyer, Robert D. ^{[1
]}

Brier, Richard A. ^{[1
]}

Hudziak, Kevin J. ^{[1
]}

Klimkowski, Valentine J. ^{[1
]}

Losada, Pablo Garcia ^{[1
]}

Mathes, Brian M. ^{[1
]}

Stout, Stephanie L. ^{[1
]}

Watson, Brian M. ^{[1
]}

Mergott, Dustin J. ^{[1
]}

机构：

[1] Lilly Corp Ctr, Lilly Res Labs, Indianapolis, IN 46285 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2015年 / 23卷 / 13期

关键词：

BACE inhibitor; Complex organic synthesis; Conformational constraint; Stereoselective; Structure-based drug design; AMYLOID PRECURSOR PROTEIN; ALZHEIMERS-DISEASE; BETA; PEPTIDE; HUMANS; MICE;

D O I：

10.1016/j.bmc.2015.04.062

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The BACE1 enzyme is a key target for Alzheimer's disease. During our BACE1 research efforts, fragment screening revealed that bicyclic thiazine 3 had low millimolar activity against BACE1. Analysis of the co-crystal structure of 3 suggested that potency could be increased through extension toward the S3 pocket and through conformational constraint of the thiazine core. Pursuit of S3-binding groups produced low micromolar inhibitor 6, which informed the S3-design for constrained analogs 7 and 8, themselves prepared via independent, multi-step synthetic routes. Biological characterization of BACE inhibitors 6-8 is described. (C) 2015 Elsevier Ltd. All rights reserved.

引用

页码：3260 / 3268

页数：9

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