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J Med Chem DOI:10.1021/jm400397x

Small-molecule inhibitors of cytokine-mediated STAT1 signal transduction in β-cells with improved aqueous solubility.

Publication TypeJournal Article
Year of Publication2013
AuthorsScully, SS, Tang, AJ, Lundh, M, Mosher, CM, Perkins, KM, Wagner, BK
JournalJ Med Chem
Volume56
Issue10
Pages4125-9
Date Published2013 May 23
ISSN1520-4804
KeywordsAniline Compounds, Apoptosis, Blotting, Western, Caspase 3, Caspase 7, Cell Line, Chemistry, Pharmaceutical, Cytokines, Humans, Indicators and Reagents, Insulin-Secreting Cells, Interferon-gamma, Phosphorylation, Signal Transduction, Solubility, STAT1 Transcription Factor, Structure-Activity Relationship, Thermodynamics, Urea
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.

DOI10.1021/jm400397x
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/23617753?dopt=Abstract

Alternate JournalJ. Med. Chem.
PubMed ID23617753
PubMed Central IDPMC3690275
Grant ListDP2 DK083048 / DK / NIDDK NIH HHS / United States
/ / Howard Hughes Medical Institute / United States