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基于结构的新型8-羟基喹啉系列作为缺氧诱导因子-1α脯氨酰羟化酶抑制剂的设计、合成及构效关系评估

Structure-based design, synthesis, and SAR evaluation of a new series of 8-hydroxyquinolines as HIF-1alpha prolyl hydroxylase inhibitors.

作者信息

Warshakoon Namal C, Wu Shengde, Boyer Angelique, Kawamoto Richard, Sheville Justin, Renock Sean, Xu Kevin, Pokross Matthew, Zhou Songtao, Winter Carol, Walter Richard, Mekel Marlene, Evdokimov Artem G

机构信息

Drug Discovery Division, Procter and Gamble Pharmaceuticals Inc., 8700 Mason-Montgomery Road, Mason, OH 45040, USA.

出版信息

Bioorg Med Chem Lett. 2006 Nov 1;16(21):5517-22. doi: 10.1016/j.bmcl.2006.08.040. Epub 2006 Aug 22.

DOI:10.1016/j.bmcl.2006.08.040
PMID:16931007
Abstract

A new series of potent 8-hydroxyquinolines was designed based on the newly resolved X-ray crystal structure of EGLN-1. Both alkyl and aryl 8-hydroxyquinoline-7-carboxyamides were good HIF-1alpha prolyl hydroxylase (EGLN) inhibitors. In subsequent VEGF induction assays, these exhibited potent VEGF activity. In addition, this class of compounds did show the ability to stabilize HIF-1alpha.

摘要

基于新解析的EGLN-1的X射线晶体结构，设计了一系列新的强效8-羟基喹啉。烷基和芳基8-羟基喹啉-7-甲酰胺都是良好的缺氧诱导因子-1α脯氨酰羟化酶（EGLN）抑制剂。在随后的血管内皮生长因子（VEGF）诱导试验中，这些化合物表现出强效的VEGF活性。此外，这类化合物确实显示出稳定缺氧诱导因子-1α的能力。

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