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

J Med Chem

Authors	Stephen Scully Alicia Tang Morten Lundh Carrie Mosher Kedar Perkins Bridget Wagner
Keywords	Humans Cell Line Apoptosis Cytokines Signal Transduction Blotting, Western Phosphorylation Aniline Compounds Caspase 3 Caspase 7 Chemistry, Pharmaceutical Indicators and Reagents Insulin-Secreting Cells Interferon-gamma STAT1 Transcription Factor Solubility 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.
Year of Publication	2013
Journal	J Med Chem
Volume	56
Issue	10
Pages	4125-9
Date Published	2013 May 23
ISSN	1520-4804
DOI	10.1021/jm400397x
PubMed ID	23617753
PubMed Central ID	PMC3690275
Links
Grant list	DP2 DK083048 / DK / NIDDK NIH HHS / United States Howard Hughes Medical Institute / United States