Abstract
We previously reported the discovery of BRD0476 (1), a small molecule generated by diversity-oriented synthesis that suppresses cytokine-induced β-cell apoptosis. Herein, we report the synthesis and biological evaluation of 1 and analogues with improved aqueous solubility. By replacing naphthyl with quinoline moieties, we prepared active analogues with up to a 1400-fold increase in solubility from 1. In addition, we demonstrated that 1 and analogues inhibit STAT1 signal transduction induced by IFN-γ.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Aniline Compounds / chemistry
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Aniline Compounds / pharmacology
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Apoptosis / drug effects
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Blotting, Western
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Caspase 3 / metabolism
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Caspase 7 / metabolism
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Cell Line
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Chemistry, Pharmaceutical
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Cytokines / antagonists & inhibitors*
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Cytokines / physiology
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Humans
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Indicators and Reagents
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Insulin-Secreting Cells / drug effects*
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Interferon-gamma / pharmacology
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Phosphorylation
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STAT1 Transcription Factor / antagonists & inhibitors*
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Signal Transduction / drug effects*
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Solubility
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Structure-Activity Relationship
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Thermodynamics
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Urea / analogs & derivatives
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Urea / chemistry
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Urea / pharmacology
Substances
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Aniline Compounds
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Cytokines
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Indicators and Reagents
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STAT1 Transcription Factor
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Interferon-gamma
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Urea
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Caspase 3
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Caspase 7