Small-Molecule Inhibitors of Cytokine-Mediated STAT1 Signal Transduction In ß-Cells With Improved Aqueous Solubility

TY - JOUR

T1 - Small-Molecule Inhibitors of Cytokine-Mediated STAT1 Signal Transduction In ß-Cells With Improved Aqueous Solubility

AU - Scully, Stephen Shane

AU - Tang, Alicia J

AU - Lundh, Morten

AU - Mosher, Carrie M

AU - Perkins, Kedar M

AU - Wagner, Bridget K

PY - 2013/5/23

Y1 - 2013/5/23

N2 - 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.

AB - 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.

U2 - 10.1021/jm400397x

DO - 10.1021/jm400397x

M3 - Journal article

C2 - 23617753

SN - 0022-2623

VL - 56

SP - 4125

EP - 4129

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 10

ER -