1. Discovery of indole-derived pyridopyrazine-1,6-dione γ-secretase modulators that target presenilin.
- Author
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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, and Verhoest PR
- Subjects
- Animals, Indoles chemistry, Rats, Amyloid Precursor Protein Secretases drug effects, Drug Discovery, Indoles pharmacology, Presenilins drug effects, Pyrazines chemistry
- 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., (Copyright © 2014 Elsevier Ltd. All rights reserved.)
- Published
- 2015
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