N-Hydroxy-3-phenyl-2-propenamides as Novel Inhibitors of Human Histone Deacetylase with in Vivo Antitumor Activity: Discovery of (2E)-N-Hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide (NVP-LAQ824)
Journal of Medicinal Chemistry2003Vol. 46(21), pp. 4609–4624
Citations Over TimeTop 10% of 2003 papers
Stacy Remiszewski, Lidia Sambucetti, Kenneth W. Bair, John Bontempo, David Cesarz, Nagarajan Chandramouli, Ru Chen, Min Rex Cheung, Susan Cornell-Kennon, Karl Dean, George Diamantidis, Dennis S. France, Michael A. Green, Kobporn Lulu Howell, Rina Kashi, Paul Kwon, Peter Lassota, Mary St. Martin, Yin Mou, Lawrence Perez, Sushil K. Sharma, Troy Smith, Eric S. Sorensen, Francis Taplin, Nancy Trogani, Richard Versace, Heather Walker, Susan Weltchek-Engler, Alexander W. Wood, Arthur Wu, Peter Atadja
Abstract
A series of N-hydroxy-3-phenyl-2-propenamides were prepared as novel inhibitors of human histone deacetylase (HDAC). These compounds were potent enzyme inhibitors, having IC(50)s or = 100 mg/kg were selected for dose-response studies in the HCT116 xenograft model. One compound, 9 (NVP-LAQ824), had significant dose-related activity in the HCT116 colon and A549 lung tumor models, high MTD, and low gross toxicity. On the basis, in part, of these properties, 9 has entered human clinical trials in 2002.
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