Synthesis and biological evaluation of lisofylline (LSF) analogs as a potential treatment for Type 1 diabetes

被引:40
作者
Cui, Peng [1 ]
Macdonald, Timothy L.
Chen, Meng
Nadler, Jerry L.
机构
[1] Univ Virginia, Dept Chem, Charlottesville, VA 22904 USA
[2] Univ Virginia, Dept Med, Div Endocrinol & Metab, Charlottesville, VA 22908 USA
关键词
type; 1; diabetes; lisofylline; LSF; LSF analogs; 5-aza-7-deazaxanthine;
D O I
10.1016/j.bmcl.2006.04.036
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Lisofylline (LSF, 1-(5-R-hydroxyhexyl)-3,7-dimethylxanthine) is an anti-inflammatory agent that protects beta-cells from Th1 cytokine-induced dysfunction and reduces the onset of Type I diabetes in non-obese diabetic (NOD) mice. Due to its low potency, poor oral bioavailability, and short half-life, the widespread clinical utility of LSF may be limited. Our goal has been to develop new agents based on the LSF structural motif that resolve the potency and pharmacokinetic liabilities of LSF. In this study, we have generated a focused library of LSF analogs that maintain the side chain (5-R-hydroxyhexyl) constant, while substituting a variety of nitrogen-containing heterocyclic substructures for the xanthine moiety of LSF. This library includes the xanthine-like (5-aza-7-deazaxanthine), as well as non-xanthine-like skeletons. The LSF analogs were evaluated in a pancreatic P-cell line for the effects on apoptosis protection and insulin release. The metabolic stability of selected compounds was also tested. (c) 2006 Elsevier Ltd. All rights reserved.
引用
收藏
页码:3401 / 3405
页数:5
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