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Discovery of Benzotriazolo[4,3-d][1,4]diazepines as Orally Active Inhibitors of BET Bromodomains.

ABSTRACT: Inhibition of the bromodomains of the BET family, of which BRD4 is a member, has been shown to decrease myc and interleukin (IL) 6 in vivo, markers that are of therapeutic relevance to cancer and inflammatory disease, respectively. Herein we report substituted benzo[b]isoxazolo[4,5-d]azepines and benzotriazolo[4,3-d][1,4]diazepines as fragment-derived novel inhibitors of the bromodomain of BRD4. Compounds from these series were potent and selective in cells, and subsequent optimization of microsomal stability yielded representatives that demonstrated dose- and time-dependent reduction of plasma IL-6 in mice.

SUBMITTER: Taylor AM

PROVIDER: S-EPMC4753545 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Discovery of Benzotriazolo[4,3-d][1,4]diazepines as Orally Active Inhibitors of BET Bromodomains.

Taylor Alexander M AM Vaswani Rishi G RG Gehling Victor S VS Hewitt Michael C MC Leblanc Yves Y Audia James E JE Bellon Steve S Cummings Richard T RT Côté Alexandre A Harmange Jean-Christophe JC Jayaram Hari H Joshi Shivangi S Lora Jose M JM Mertz Jennifer A JA Neiss Adrianne A Pardo Eneida E Nasveschuk Christopher G CG Poy Florence F Sandy Peter P Setser Jeremy W JW Sims Robert J RJ Tang Yong Y Albrecht Brian K BK

ACS medicinal chemistry letters 20150325 2

Inhibition of the bromodomains of the BET family, of which BRD4 is a member, has been shown to decrease myc and interleukin (IL) 6 in vivo, markers that are of therapeutic relevance to cancer and inflammatory disease, respectively. Herein we report substituted benzo[b]isoxazolo[4,5-d]azepines and benzotriazolo[4,3-d][1,4]diazepines as fragment-derived novel inhibitors of the bromodomain of BRD4. Compounds from these series were potent and selective in cells, and subsequent optimization of micros ...[more]

PMID: 26985289

Dataset Information

Discovery of Benzotriazolo[4,3-d][1,4]diazepines as Orally Active Inhibitors of BET Bromodomains.

Publications

Discovery of Benzotriazolo[4,3-d][1,4]diazepines as Orally Active Inhibitors of BET Bromodomains.

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