Structure-activity relationships of N-hydroxyurea 5-lipoxygenase inhibitors

被引：35

作者：

Stewart, AO ^{[1
]}

Bhatia, PA ^{[1
]}

Martin, JG ^{[1
]}

Summers, JB ^{[1
]}

Rodriques, KE ^{[1
]}

Martin, MB ^{[1
]}

Holms, JH ^{[1
]}

Moore, JL ^{[1
]}

Craig, RA ^{[1
]}

Kolasa, T ^{[1
]}

Ratajczyk, JD ^{[1
]}

Mazdiyasni, H ^{[1
]}

Kerdesky, FAJ ^{[1
]}

DeNinno, SL ^{[1
]}

Maki, RG ^{[1
]}

Bouska, JB ^{[1
]}

Young, PR ^{[1
]}

Lanni, C ^{[1
]}

Bell, RL ^{[1
]}

Carter, GW ^{[1
]}

Brooks, CDW ^{[1
]}

机构：

[1] ABBOTT LABS, IMMUNOSCI RES, ABBOTT PK, IL 60064 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 1997年 / 40卷 / 13期

关键词：

D O I：

10.1021/jm9700474

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The discovery of second generation N-hydroxyurea 5-lipoxygenase inhibitors was accomplished through the development of a broad structure-activity relationship (SAR) study. This study identified requirements for improving potency and also extending duration by limiting metabolism. Potency could be maintained by the incorporation of heterocyclic templates substituted with selected lipophilic substituents. Duration of inhibition after oral administration was optimized by identification of structural features in the proximity of the N-hydroxyurea which correlated to low in vitro glucuronidation rates. Furthermore, the rate of in vitro glucuronidation was shown to be stereoselective for certain analogs. (R)-N-[3-[5-(4-Fluorophenoxy)-2-furyl]-1-methyl-2-propynyl]-N-hy- droxyurea (17c) was identified and selected for clinical development.

引用

页码：1955 / 1968

页数：14

共 42 条

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