Pharmacological characterization of SC-57461A (3-[methyl[3-[4-(phenylmethyl)phenoxy]propyl]amino]propanoic acid HCl), a potent and selective inhibitor of leukotriene A4 hydrolase I:: In vitro studies

被引：35

作者：

Askonas, LJ ^{[1
]}

Kachur, JF ^{[1
]}

Villani-Price, D ^{[1
]}

Liang, CDD ^{[1
]}

Russell, MA ^{[1
]}

Smith, WG ^{[1
]}

机构：

[1] Pharmacia Res & Dev, Skokie, IL 60077 USA

来源：

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS | 2002年 / 300卷 / 02期

关键词：

D O I：

10.1124/jpet.300.2.577

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

Leukotriene (LT) B-4 is an inflammatory mediator that has been implicated in the pathogenesis of various diseases, including inflammatory bowel disease and psoriasis. As the rate-limiting step for LTB4 production, LTA(4) hydrolase represents an attractive target for therapeutic agents that interfere with LTB4 production. In the present study we evaluated a chemically novel compound designated SC-57461A (3-[methyl[3-[4-(phenylmethyl)phenoxy] propyl]amino] propanoic acid HCI) as an inhibitor of LTA(4) hydrolase. Pharmacological comparisons are made to its free acid SC-57461. SC-57461A is a potent competitive inhibitor of recombinant human LTA(4) hydrolase when either LTA(4) (IC50 = 2.5 nM, K-i = 23 nM) or peptide substrates (IC50 = 27 nM) are used. In human whole blood, the IC50 for calcium ionophore-induced LTB4 production was 49 nM, indicative of good cell penetration. Whole blood production of the cyclooxygenase metabolite thromboxane B-2 was not affected. SC-57461A was also active in-several other species, including mouse, rat, dog, and rhesus monkey. The data indicate that SC-57461A is a potent and selective inhibitor of LTA(4) hydrolase.

引用

页码：577 / 582

页数：6

共 36 条

[1] Pharmacological characterization of SC-57461A (3-[methyl[3-[4-(phenylmethyl)phenoxy]propyl]amino]propanoic acid HCl), a potent and selective inhibitor of leukotriene A4 hydrolase I:: In vitro studies [J].