2. Academic Validation
  3. Design, synthesis, and pharmacological evaluation of a novel series of pyridopyrazine-1,6-dione γ-secretase modulators

Design, synthesis, and pharmacological evaluation of a novel series of pyridopyrazine-1,6-dione γ-secretase modulators

  • J Med Chem. 2014 Feb 13;57(3):1046-62. doi: 10.1021/jm401782h.
Martin Pettersson 1,  Douglas S Johnson,  Chakrapani Subramanyam,  Kelly R Bales,  Christopher W am Ende,  Benjamin A Fish,  Michael E Green,  Gregory W Kauffman,  Patrick B Mullins,  Thayalan Navaratnam,  Subas M Sakya,  Cory M Stiff,  Tuan P Tran,  Longfei Xie,  Liming Zhang,  Leslie R Pustilnik,  Beth C Vetelino,  Kathleen M Wood,  Nikolay Pozdnyakov,  Patrick R Verhoest,  Christopher J O'Donnell
Affiliations

Affiliation

  • 1 Pfizer Worldwide Research & Development , 610 Main Street, Cambridge, Massachusetts 02139, United States.
PMID: 24428186 DOI: 10.1021/jm401782h
Abstract

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.

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