Discovery of ethyl ketone-based HDACs 1, 2, and 3 selective inhibitors for HIV latency reactivation

被引：20

作者：

Yu, Wensheng ^{[1
]}

Liu, Jian ^{[1
]}

Yu, Younong ^{[1
]}

Zhang, Vivian ^{[1
]}

Clausen, Dane ^{[1
]}

Kelly, Joseph ^{[1
]}

Wolkenberg, Scott ^{[2
]}

Beshore, Douglas ^{[2
]}

Duffy, Joseph L. ^{[1
]}

Chung, Christine C. ^{[1
]}

Myers, Robert W. ^{[1
]}

Klein, Daniel J. ^{[2
]}

Fells, James ^{[2
]}

Holloway, Kate ^{[2
]}

Wu, Jin ^{[1
]}

Wu, Guoxin ^{[2
]}

Howell, Bonnie J. ^{[2
]}

Barnard, Richard J. O. ^{[2
]}

Kozlowski, Joseph ^{[1
]}

机构：

[1] Merck & Co Inc, 2000 Galloping Hill Rd, Kenilworth, NJ 07033 USA

[2] Merck & Co Inc, 770 Sumneytown Pike, West Point, PA 19486 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2020年 / 30卷 / 13期

关键词：

HDAC inhibitor; HIV latency; Zinc binding group; Shock and kill; 2C4; cells; HDACs; 1; 2; 3; 6; 8; HIV latency reversing agent; HISTONE DEACETYLASE INHIBITOR; ANTIRETROVIRAL THERAPY;

D O I：

10.1016/j.bmcl.2020.127197

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A novel series of ethyl ketone based HDACs 1, 2, and 3 selective inhibitors have been identified with good enzymatic and cellular activity and high selectivity over HDACs 6 and 8. These inhibitors contain a spirobicyclic group in the amide region. Compound 13 stands out as a lead due to its good potency, high selectivity, and reasonable rat and dog PK. Compounds 33 and 34 show good potency and rat PK profiles as well.

引用

页数：8

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