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

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Stewart AO, Bhatia PA, Martin JG, Summers JB, Rodriques KE, Martin MB, Holms JH, Moore JL, Craig RA, Kolasa T, Ratajczyk JD, Mazdiyasni H, Kerdesky FA, DeNinno SL, Maki RG, Bouska JB, Young PR, Lanni C, Bell RL, Carter GW, Brooks CD

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

J Med Chem. 1997 Jun 20;40(13):1955-68.

PubMed ID

9207936 [ View in PubMed

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Abstract

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-hydroxyure a (17c) was identified and selected for clinical development.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Zileuton	Arachidonate 5-lipoxygenase	IC 50 (nM)	740	N/A	N/A	Details