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

Herein we describe design strategies that led to the discovery of novel pyridopyrazine-1,6-dione gamma-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 A beta 42 was achieved in a rat efficacy model when dosed orally at 30 mg/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 gamma-secretase complex. (C) 2014 Elsevier Ltd. All rights reserved.