Design, synthesis, and activity of 2,6-diphenoxypyridine-derived factor Xa inhibitors

被引：40

作者：

Phillips, G ^{[1
]}

Davey, DD ^{[1
]}

Eagen, KA ^{[1
]}

Koovakkat, SE ^{[1
]}

Liang, A ^{[1
]}

Ng, HP ^{[1
]}

Pinkerton, M ^{[1
]}

Trinh, L ^{[1
]}

Whitlow, M ^{[1
]}

Beatty, AM ^{[1
]}

Morrissey, MM ^{[1
]}

机构：

[1] Berlex Biosci, Discovery Res, Richmond, CA 94804 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 1999年 / 42卷 / 10期

关键词：

D O I：

10.1021/jm980667k

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A novel series of 2,6-diphenoxypyridines has been designed to inhibit factor Xa, a serine protease strategically located in the coagulation cascade. The evolution from the photochemically unstable bisamidine (Z,Z)-BABCH to potent bisamidine compounds with a pyridine heterocycle as the core scaffold has been achieved. The most potent compound in the series, 6h, has a K-i for human factor Xa of 12 nM. The selectivity of 6h against bovine trypsin and human thrombin was greater than 90- and 1000-fold, respectively. Two proposed modes of binding of 6h Do factor Xa are made based on the crystal structures of 6h by itself and of 6h bound to bovine trypsin.

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收藏

页码：1749 / 1756

页数：8

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