The discovery of 6-amino nicotinamides as potent and selective histone deacetylase inhibitors

被引：47

作者：

Hamblett, Christopher L.

Methot, Joey L.

Mampreian, Dawn M.

Sloman, David L.

Stanton, Matthew G.

Kral, Astrid M.

Fleming, Judith C.

Cruz, Jonathan C.

Chenard, Melissa

Ozerova, Nicole

Hitz, Anna M.

Wang, Hongmei

Deshmukh, Sujal V.

Nazef, Nalm

Harsch, Andreas

Hughes, Bethany

Dahlberg, William K.

Szewczak, Alex A.

Middleton, Richard E.

Mosley, Ralph T.

Secrist, J. Paul

Miller, Thomas A.

机构：

[1] Merck Res Labs, Dept Drug Design & Optimizat Med Chem, Boston, MA 02115 USA

[2] Merck Res Labs, Dept Canc Biol & Therapeut, Boston, MA 02115 USA

[3] Merck Res Labs, Dept Pharmacol, Boston, MA 02115 USA

[4] Merck Res Labs, Dept Drug Design & Optimizat Drug Metab & Pharmac, Boston, MA 02115 USA

[5] Merck Res Labs, Dept Drug Design & Optimizat Automated Lead Optim, Boston, MA 02115 USA

[6] Merck Res Labs, Dept Med Chem, Rahway, NJ 07065 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2007年 / 17卷 / 19期

关键词：

epigenetics; histone acetylation; histone deacetylases; nicotinamides; benzamides;

D O I：

10.1016/j.bmcl.2007.08.023

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

This communication highlights the development of a nicotinamide series of histone deacetylase inhibitors within the benzamide structural class. Extensive exploration around the nicotinamide core led to the discovery of a class I selective HDAC inhibitor that possesses excellent intrinsic and cell-based potency, acceptable ancillary pharmacology, favorable pharmacokinetics, sustained pharmacodynamics in vitro, and achieves in vivo efficacy in an HCT116 xenograft model. (C) 2007 Elsevier Ltd. All rights reserved.

引用

页码：5300 / 5309

页数：10

共 39 条

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