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

被引：22

作者：

Bowers, Simeon ^{[1
]}

Truong, Anh P. ^{[1
]}

Ye, Michael ^{[1
]}

Aubele, Danielle L. ^{[1
]}

Sealy, Jennifer M. ^{[1
]}

Neitz, R. Jeffrey ^{[1
]}

Hom, Roy K. ^{[1
]}

Chan, Wayman ^{[1
]}

Dappen, Michael S. ^{[1
]}

Galemmo, Robert A., Jr. ^{[1
]}

Konradi, Andrei W. ^{[1
]}

Sham, Hing L. ^{[1
]}

Zhu, Yong L. ^{[2
]}

Beroza, Paul ^{[2
]}

Tonn, George ^{[3
]}

Zhang, Heather ^{[3
]}

Hoffman, Jennifer ^{[3
]}

Motter, Ruth ^{[3
]}

Fauss, Donald ^{[3
]}

Tanaka, Pearl ^{[3
]}

Bova, Michael P. ^{[3
]}

Ren, Zhao ^{[3
]}

Tam, Danny ^{[3
]}

Ruslim, Lany ^{[3
]}

Baker, Jeanne ^{[3
]}

Pandya, Deepal ^{[3
]}

Diep, Linnea ^{[3
]}

Fitzgerald, Kent ^{[3
]}

Artis, Dean R. ^{[3
]}

Anderson, John P. ^{[3
]}

Bergeron, Marcelle ^{[3
]}

机构：

[1] Elan Pharmaceut, Dept Chem Sci, San Francisco, CA 94080 USA

[2] Elan Pharmaceut, Dept Mol Design, San Francisco, CA 94080 USA

[3] Elan Pharmaceut, Dept Pharmacol Sci, San Francisco, CA 94080 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2013年 / 23卷 / 09期

关键词：

Polo like kinase; PLK inhibitor; Parkinson's disease; Alpha-synuclein; ALPHA-SYNUCLEIN; PHOSPHORYLATION;

D O I：

10.1016/j.bmcl.2013.02.065

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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-alpha-synuclein levels in the cerebral cortex. (C) 2013 Elsevier Ltd. All rights reserved.

引用

页码：2743 / 2749

页数：7

共 16 条

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