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Discovery of indole-derived pyridopyrazine-1,6-dione γ-secretase modulators that target presenilin.

Abstract：

:Herein we describe design strategies that led to the discovery of novel pyridopyrazine-1,6-dione γ-secretase modulators (GSMs) incorporating an indole motif as a heterocyclic replacement for a naphthyl moiety that was present in the original lead 9. Tactics involving parallel medicinal chemistry and in situ monomer synthesis to prepare focused libraries are discussed. Optimized indole GSM 29 exhibited good alignment of in vitro potency and physicochemical properties, and moderate reduction of brain Aβ42 was achieved in a rat efficacy model when dosed orally at 30mg/kg. Labeling experiments using a clickable, indole-derived GSM photoaffinity probe demonstrated that this series binds to the presenilin N-terminal fragment (PS1-NTF) of the γ-secretase complex.

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

Pettersson M,Johnson DS,Humphrey JM,Am Ende CW,Evrard E,Efremov I,Kauffman GW,Stepan AF,Stiff CM,Xie L,Bales KR,Hajos-Korcsok E,Murrey HE,Pustilnik LR,Steyn SJ,Wood KM,Verhoest PR

doi

10.1016/j.bmcl.2014.12.059

subject

Has Abstract

pub_date

2015-02-15 00:00:00

pages

908-13

issue

4

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(14)01367-5

journal_volume

25

pub_type

杂志文章

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