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Discovery of 4-aminomethylphenylacetic acids as γ-secretase modulators via a scaffold design approach.

Abstract：

:Starting from literature examples of nonsteroidal anti-inflammatory drugs (NSAIDs)-type carboxylic acid γ-secretase modulators (GSMs) and using a scaffold design approach, we identified 4-aminomethylphenylacetic acid 4 with a desirable γ-secretase modulation profile. Scaffold optimization led to the discovery of a novel chemical series, represented by 6b, having improved brain penetration. Further SAR studies provided analog 6q that exhibited a good pharmacological profile. Oral administration of 6q significantly reduced brain Aβ42 levels in mice and rats.

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

Xin Z,Peng H,Zhang A,Talreja T,Kumaravel G,Xu L,Rohde E,Jung MY,Shackett MN,Kocisko D,Chollate S,Dunah AW,Snodgrass-Belt PA,Arnold HM,Taveras AG,Rhodes KJ,Scannevin RH

doi

10.1016/j.bmcl.2011.10.047

subject

Has Abstract

pub_date

2011-12-15 00:00:00

pages

7277-80

issue

24

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(11)01445-4

journal_volume

21

pub_type

杂志文章

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