Discovery of potent, selective sulfonylfuran urea endothelial lipase inhibitors
Discovery of potent, selective sulfonylfuran urea endothelial lipase inhibitors
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DOI：
10.1016/j.bmcl.2008.11.033
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发表时间：
2009-01-01
影响因子：
2.7
通讯作者：
Jaye, Michael C.
中科院分区：
文献类型：
--
作者：
Goodman, Krista B.;Bury, Michael J.;Jaye, Michael C.
内皮脂肪酶(EL)活性与高密度脂蛋白分解代谢、血管炎症和动脉粥样硬化形成有关，因此，抑制剂有望用于心血管疾病的治疗。在高通量筛选活动中，磺酰呋喃尿素1被确定为一种有效的、非选择性的EL抑制剂。进行了领先的优化工作，以提高效力和选择性，并确定了导致改善LPL选择性的修改。进行了放射性标记研究，以确定这些抑制剂的作用机制，最终证明它们是不可逆转的抑制剂。(C)2008爱思唯尔有限公司。保留所有权利。
Endothelial lipase (EL) activity has been implicated in HDL catabolism, vascular inflammation, and atherogenesis, and inhibitors are therefore expected to be useful for the treatment of cardiovascular disease. Sulfonylfuran urea 1 was identified in a high-throughput screening campaign as a potent and non-selective EL inhibitor. A lead optimization effort was undertaken to improve potency and selectivity, and modifications leading to improved LPL selectivity were identified. Radiolabeling studies were undertaken to establish the mechanism of action for these inhibitors, which were ultimately demonstrated to be irreversible inhibitors. (C) 2008 Elsevier Ltd. All rights reserved.