|
|||||
|
|
Design and synthesis of highly selective,orally active Polo-like kinase-2 (Plk-2) inhibitors |
|
| Authors: | Simeon Bowers Anh P Truong Michael Ye Danielle L Aubele Jennifer M Sealy R Jeffrey Neitz Roy K Hom Wayman Chan Michael S Dappen Robert A Galemmo Andrei W Konradi Hing L Sham Yong L Zhu Paul Beroza George Tonn Heather Zhang Jennifer Hoffman Ruth Motter Marcelle Bergeron |
| Institution: | 1. Department of Chemical Sciences, Elan Pharmaceuticals, 180 Oyster Point Boulevard, South San Francisco, CA 94080, USA;2. Department of Molecular Design, Elan Pharmaceuticals, 180 Oyster Point Boulevard, South San Francisco, CA 94080, USA;3. Department of Pharmacological Sciences, Elan Pharmaceuticals, 180 Oyster Point Boulevard, South San Francisco, CA 94080, USA |
| Abstract: | 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. |
| Keywords: | |
| 本文献已被 ScienceDirect 等数据库收录！ | |