当前位置： SCI文献检索 > JOURNAL OF MEDICINAL CHEMISTRY期刊下所有文献 > Lead optimization and modulation of hERG activity in a series of aminooxazoline xanthene β-site amyloid precursor protein cleaving enzyme (BACE1) inhibitors.

Lead optimization and modulation of hERG activity in a series of aminooxazoline xanthene β-site amyloid precursor protein cleaving enzyme (BACE1) inhibitors.

Abstract：

:The optimization of a series of aminooxazoline xanthene inhibitors of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is described. An early lead compound showed robust Aβ lowering activity in a rat pharmacodynamic model, but advancement was precluded by a low therapeutic window to QTc prolongation in cardiovascular models consistent with in vitro activity on the hERG ion channel. While the introduction of polar groups was effective in reducing hERG binding affinity, this came at the expense of higher than desired Pgp-mediated efflux. A balance of low Pgp efflux and hERG activity was achieved by lowering the polar surface area of the P3 substituent while retaining polarity in the P2' side chain. The introduction of a fluorine in position 4 of the xanthene ring improved BACE1 potency (5-10-fold). The combination of these optimized fragments resulted in identification of compound 40, which showed robust Aβ reduction in a rat pharmacodynamic model (78% Aβ reduction in CSF at 10 mg/kg po) and also showed acceptable cardiovascular safety in vivo.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Epstein O,Bryan MC,Cheng AC,Derakhchan K,Dineen TA,Hickman D,Hua Z,Human JB,Kreiman C,Marx IE,Weiss MM,Wahl RC,Wen PH,Whittington DA,Wood S,Zheng XM,Fremeau RT Jr,White RD,Patel VF

doi

10.1021/jm501266w

subject

Has Abstract

pub_date

2014-12-11 00:00:00

pages

9796-810

issue

23

eissn

0022-2623

issn

1520-4804

journal_volume

57

pub_type

杂志文章

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