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

• 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
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2018.05.021

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•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.