1402001-78-8Relevant articles and documents
Design, synthesis, and pharmacological evaluation of a novel series of pyridopyrazine-1,6-dione γ-secretase modulators
Pettersson, Martin,Johnson, Douglas S.,Subramanyam, Chakrapani,Bales, Kelly R.,Am Ende, Christopher W.,Fish, Benjamin A.,Green, Michael E.,Kauffman, Gregory W.,Mullins, Patrick B.,Navaratnam, Thayalan,Sakya, Subas M.,Stiff, Cory M.,Tran, Tuan P.,Xie, Longfei,Zhang, Liming,Pustilnik, Leslie R.,Vetelino, Beth C.,Wood, Kathleen M.,Pozdnyakov, Nikolay,Verhoest, Patrick R.,O'Donnell, Christopher J.
, p. 1046 - 1062 (2014)
Herein we describe the design and synthesis of a novel series of γ-secretase modulators (GSMs) that incorporates a pyridopiperazine-1,6- dione ring system. To align improved potency with favorable ADME and in vitro safety, we applied prospective physicochemical property-driven design coupled with parallel medicinal chemistry techniques to arrive at a novel series containing a conformationally restricted core. Lead compound 51 exhibited good in vitro potency and ADME, which translated into a favorable in vivo pharmacokinetic profile. Furthermore, robust reduction of brain Aβ42 was observed in guinea pig at 30 mg/kg dosed orally. Through chemical biology efforts involving 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 insight into the binding site of this series of GSMs.
