Design and synthesis of highly selective, orally active Polo-like kinase-2 (Plk-2) inhibitors.

@article{Bowers2013DesignAS,
  title={Design and synthesis of highly selective, orally active Polo-like kinase-2 (Plk-2) inhibitors.},
  author={Simeon Bowers and Anh P. Truong and Michael J Ye and Danielle L. Aubele and Jennifer M. Sealy and R. Jeffrey Neitz and Roy Kay Hom and Wayman Chan and Michael S. Dappen and Robert Anthony Galemmo and Andrei William Konradi and Hing Leung Sham and Yong Liang Zhu and Paul Beroza and George Tonn and Heather Zhang and Jennifer Ruth Hoffman and Ruth Motter and Donald Fauss and Pearl Tanaka and Michael P. Bova and Zhao Hua Ren and Danny W H Tam and Lany Ruslim and Jeanne E. Baker and Deepal Pandya and Linnea Diep and Kent Fitzgerald and Dean R. Artis and John Patrick Anderson and Marcelle Bergeron},
  journal={Bioorganic & medicinal chemistry letters},
  year={2013},
  volume={23 9},
  pages={
          2743-9
        }
}
Polo-like kinase-2 (Plk-2) is a potential therapeutic target for Parkinson's disease and this Letter describes the SAR of a series of dihydropteridinone based Plk-2 inhibitors. By optimizing both the N-8 substituent and the biaryl region of the inhibitors we obtained single digit nanomolar compounds such as 37 with excellent selectivity for Plk-2 over Plk-1. When dosed orally in rats, compound 37 demonstrated a 41-45% reduction of pS129-α-synuclein levels in the cerebral cortex. 
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