Lead optimization of apyrazolo[1,5-a]pyrimidin-7(4H)-one scaffold to identify potent, selective and orally bioavailable KDM5 inhibitors suitable for in vivo biological studies

被引：34

作者：

Liang, Jun ^{[1
]}

Zhang, Birong ^{[1
]}

Labadie, Sharada ^{[1
]}

Ortwine, Daniel F. ^{[1
]}

Vinogradova, Maia ^{[1
]}

Kiefer, James R. ^{[1
]}

Gehling, Victor S. ^{[2
]}

Harmange, Jean-Christophe ^{[2
]}

Cummings, Richard ^{[2
]}

Lai, Tommy ^{[3
]}

Liao, Jiangpeng ^{[3
]}

Zheng, Xiaoping ^{[3
]}

Liu, Yichin ^{[1
]}

Gustafson, Amy ^{[1
]}

Van der Porten, Erica ^{[1
]}

Mao, Weifeng ^{[3
]}

Liederer, Bianca M. ^{[1
]}

Deshmukh, Gauri ^{[1
]}

Classon, Marie ^{[1
]}

Trojer, Patrick ^{[2
]}

Dragovich, Peter S. ^{[1
]}

Murray, Lesley ^{[1
]}

机构：

[1] Genentech Inc, 1 DNA Way, San Francisco, CA 94080 USA

[2] Constellat Pharmaceut Inc, 215 First St,Suite 200, Cambridge, MA 02142 USA

[3] WuXi AppTec, 288 Fute Zhong Rd, Shanghai 200131, Peoples R China

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2016年 / 26卷 / 16期

关键词：

Histone demethylase; KDM5; Selective KDM5 inhibitors; Epigenetics; Drug resistance; Lead optimization; CELL PENETRANT INHIBITORS; DEMETHYLASE INHIBITORS; LYSINE DEMETHYLASES; HISTONE; DERIVATIVES; METHYLATION; INHERITANCE; MECHANISMS; FAMILIES;

D O I：

10.1016/j.bmcl.2016.06.078

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Starting with a lead [1,5-a]pyrimidin-7(4H)-one-containing molecule (1), we generated potent, selective and orally bioavailable KDM5 inhibitors. Using structure- and property-based approaches, we designed 48 with improved cell potency (PC9 H3K4Me3 EC50 = 0.34 mu M). Furthermore, 48 maintained suitable physiochemical properties and displayed an excellent pharmacokinetic (PK) profile in mice. When dosed orally in mice at 50 mg/kg twice a day (BID), 48 showed an unbound maximal plasma concentration (C-max) >15-fold over its cell EC50, thereby providing a robust chemical probe for studying KDM5 biological functions in vivo. (C) 2016 Elsevier Ltd. All rights reserved.

引用

页码：4036 / 4041

页数：6

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