Discovery of novel N-hydroxy-2-arylisoindoline-4-carboxamides as potent and selective inhibitors of HDAC11

[Display omitted] •Identified novel, potent, and selective first-in-class inhibitors of HDAC11.•Synthesis and structure activity relationships of compounds are reported.•FT895 displays promising cellular activity and pharmacokinetic properties.•FT895 is a valuable tool for further study of the biolo...

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Published in:	Bioorganic & medicinal chemistry letters Vol. 28; no. 12; pp. 2143 - 2147
Main Authors:	Martin, Matthew W., Lee, Jennifer Y., Lancia, David R., Ng, Pui Yee, Han, Bingsong, Thomason, Jennifer R., Lynes, Maureen S., Marshall, C. Gary, Conti, Chiara, Collis, Alan, Morales, Monica Alvarez, Doshi, Kshama, Rudnitskaya, Aleksandra, Yao, Lili, Zheng, Xiaozhang
Format:	Journal Article
Language:	English
Published:	England Elsevier Ltd 01-07-2018
Subjects:	Animals Dose-Response Relationship, Drug Drug Discovery Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology HDAC11 HDACs Histone Deacetylases - metabolism Humans Hydroxamic acid Inflammation Isoindoles - chemical synthesis Isoindoles - chemistry Isoindoles - pharmacology Isoindoline Male Mice Mice, Inbred BALB C Mice, Nude Molecular Structure Oncology Recombinant Proteins - metabolism Structure-Activity Relationship Hydroxamic acid Oncology Inflammation HDACs Isoindoline HDAC11
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Abstract	[Display omitted] •Identified novel, potent, and selective first-in-class inhibitors of HDAC11.•Synthesis and structure activity relationships of compounds are reported.•FT895 displays promising cellular activity and pharmacokinetic properties.•FT895 is a valuable tool for further study of the biology of HDAC11. N-Hydroxy-2-arylisoindoline-4-carboxamides are potent and selective inhibitors of HDAC11. The discovery, synthesis, and structure activity relationships of this novel series of inhibitors are reported. An advanced analog (FT895) displays promising cellular activity and pharmacokinetic properties that make it a useful tool to study the biology of HDAC11 and its potential use as a therapeutic target for oncology and inflammation indications.
AbstractList	N-Hydroxy-2-arylisoindoline-4-carboxamides are potent and selective inhibitors of HDAC11. The discovery, synthesis, and structure activity relationships of this novel series of inhibitors are reported. An advanced analog (FT895) displays promising cellular activity and pharmacokinetic properties that make it a useful tool to study the biology of HDAC11 and its potential use as a therapeutic target for oncology and inflammation indications. [Display omitted] •Identified novel, potent, and selective first-in-class inhibitors of HDAC11.•Synthesis and structure activity relationships of compounds are reported.•FT895 displays promising cellular activity and pharmacokinetic properties.•FT895 is a valuable tool for further study of the biology of HDAC11. N-Hydroxy-2-arylisoindoline-4-carboxamides are potent and selective inhibitors of HDAC11. The discovery, synthesis, and structure activity relationships of this novel series of inhibitors are reported. An advanced analog (FT895) displays promising cellular activity and pharmacokinetic properties that make it a useful tool to study the biology of HDAC11 and its potential use as a therapeutic target for oncology and inflammation indications.
Author	Martin, Matthew W. Collis, Alan Ng, Pui Yee Lancia, David R. Doshi, Kshama Lee, Jennifer Y. Morales, Monica Alvarez Han, Bingsong Lynes, Maureen S. Marshall, C. Gary Rudnitskaya, Aleksandra Zheng, Xiaozhang Thomason, Jennifer R. Yao, Lili Conti, Chiara
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Snippet	[Display omitted] •Identified novel, potent, and selective first-in-class inhibitors of HDAC11.•Synthesis and structure activity relationships of compounds are... N-Hydroxy-2-arylisoindoline-4-carboxamides are potent and selective inhibitors of HDAC11. The discovery, synthesis, and structure activity relationships of...
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SubjectTerms	Animals Dose-Response Relationship, Drug Drug Discovery Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology HDAC11 HDACs Histone Deacetylases - metabolism Humans Hydroxamic acid Inflammation Isoindoles - chemical synthesis Isoindoles - chemistry Isoindoles - pharmacology Isoindoline Male Mice Mice, Inbred BALB C Mice, Nude Molecular Structure Oncology Recombinant Proteins - metabolism Structure-Activity Relationship
Title	Discovery of novel N-hydroxy-2-arylisoindoline-4-carboxamides as potent and selective inhibitors of HDAC11
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