- ARYL AND HETEROARYL FUSED LACTAMS
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This invention relates to compounds of general formula (I) in which R1, R2, U, V, L, M, R5, m, X, Y and Z are as defined herein, and the pharmaceutically acceptable salts thereof, to pharmaceutical compositions comprising such compounds and salts, and to methods of using such compounds, salts and compositions for the treatment of abnormal cell growth, including cancer.
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Paragraph 0777; 0778
(2014/07/08)
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- Design, synthesis, and pharmacological evaluation of a novel series of pyridopyrazine-1,6-dione γ-secretase modulators
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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.
- 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.
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p. 1046 - 1062
(2014/03/21)
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