Design, Synthesis, and PharmacologicalEvaluationof a Novel Series of Pyridopyrazine-1,6-dione γ-SecretaseModulators.

Hereinwe describe the design and synthesis of a novel series ofγ-secretase modulators (GSMs) that incorporates a pyridopiperazine-1,6-dionering system. To align improved potency with favorable ADME and invitro safety, we applied prospective physicochemical property-drivendesign coupled with parallel medicinal chemistry techniques to arriveat a novel series containing a conformationally restricted core. Leadcompound 51exhibited good in vitro potency and ADME,which translated into a favorable in vivo pharmacokinetic profile.Furthermore, robust reduction of brain Aβ42 was observed inguinea pig at 30 mg/kg dosed orally. Through chemical biology effortsinvolving the design and synthesis of a clickable photoreactive probe,we demonstrated specific labeling of the presenilin N-terminal fragment(PS1-NTF) within the γ-secretase complex, thus gaining insightinto the binding site of this series of GSMs. [ABSTRACT FROM AUTHOR]