Design, Synthesis, and Pharmacological Evaluation of a Novel Series of Pyridopyrazine-1,6-dione γ-Secretase Modulators

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• 作者：Martin Pettersson ; 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
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：February 13, 2014
• 年：2014
• 卷：57
• 期：3
• 页码：1046-1062
• 全文大小：579K
• ISSN：1520-4804

文摘

Herein we describe the design and synthesis of a novel series of 纬-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 A尾42 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 纬-secretase complex, thus gaining insight into the binding site of this series of GSMs.