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Design, synthesis, and pharmacological evaluation of a novel series of pyridopyrazine-1,6-dione γ-secretase modulators. 2014
Martin Pettersson, and
Douglas S Johnson, and
Chakrapani Subramanyam, and
Kelly R Bales, and
Christopher W am Ende, and
Benjamin A Fish, and
Michael E Green, and
Gregory W Kauffman, and
Patrick B Mullins, and
Thayalan Navaratnam, and
Subas M Sakya, and
Cory M Stiff, and
Tuan P Tran, and
Longfei Xie, and
Liming Zhang, and
Leslie R Pustilnik, and
Beth C Vetelino, and
Kathleen M Wood, and
Nikolay Pozdnyakov, and
Patrick R Verhoest, and
Christopher J O'Donnell
Pfizer Worldwide Research & Development , 610 Main Street, Cambridge, Massachusetts 02139, United States.
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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Gregory W Kauffman, and
Patrick B Mullins, and
Thayalan Navaratnam, and
Subas M Sakya, and
Cory M Stiff, and
Tuan P Tran, and
Longfei Xie, and
Liming Zhang, and
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Kelly R Bales, and
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Benjamin A Fish, and
Michael E Green, and
Gregory W Kauffman, and
Patrick B Mullins, and
Thayalan Navaratnam, and
Subas M Sakya, and
Cory M Stiff, and
Tuan P Tran, and
Longfei Xie, and
Liming Zhang, and
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Douglas S Johnson, and
Chakrapani Subramanyam, and
Kelly R Bales, and
Christopher W am Ende, and
Benjamin A Fish, and
Michael E Green, and
Gregory W Kauffman, and
Patrick B Mullins, and
Thayalan Navaratnam, and
Subas M Sakya, and
Cory M Stiff, and
Tuan P Tran, and
Longfei Xie, and
Liming Zhang, and
Leslie R Pustilnik, and
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