Dihydroxyphenylisoindoline Amides as Orally Bioavailable Inhibitors of the Heat Shock Protein 90 (Hsp90) Molecular Chaperone
Journal of Medicinal Chemistry2009Vol. 53(1), pp. 499–503
Citations Over TimeTop 10% of 2009 papers
Pei‐Pei Kung, Buwen Huang, Gang Zhang, Joe Z. Zhou, Jeff Wang, Jennifer A. Digits, Judith Skaptason, Shinji Yamazaki, David Neul, Michael Zientek, Jeff Elleraas, Pramod P. Mehta, Min-Jean Yin, Michael J. Hickey, K.S. Gajiwala, Caroline Rodgers, Jay F. Davies, Michael R. Gehring
Abstract
The discovery and optimization of potency and metabolic stability of a novel class of dihyroxyphenylisoindoline amides as Hsp90 inhibitors are presented. Optimization of a screening hit using structure-based design and modification of log D and chemical structural features led to the identification of a class of orally bioavailable non-quinone-containing Hsp90 inhibitors. This class is exemplified by 14 and 15, which possess improved cell potency and pharmacokinetic profiles compared with the original screening hit.
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