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
  • 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.