173095-25-5Relevant academic research and scientific papers
Structure-activity relationships of N-hydroxyurea 5-lipoxygenase inhibitors
Stewart, Andrew O.,Bhatia, Pramila A.,Martin, Jonathan G.,Summers, James B.,Rodriques, Karen E.,Martin, Michael B.,Holms, James H.,Moore, Jimmie L.,Craig, Richard A.,Kolasa, Teodozyj,Ratajczyk, James D.,Mazdiyasni, Hormoz,Kerdesky, Francis A. J.,DeNinno, Shari L.,Maki, Robert G.,Bouska, Jennifer B.,Young, Patrick R.,Lanni, Carmine,Bell, Randy L.,Carter, George W.,Brooks, Clint D. W.
, p. 1955 - 1968 (2007/10/03)
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-hydroxyurea (17c) was identified and selected for clinical development.
(R)-(+)-N-[3-[5-[(4-fluorophenyl)methyl]-2-thienyl]-1-methyl-2-propynyl]- N-hydroxyurea (ABT-761), a second-generation 5-lipoxygenase inhibitor
Brooks,Stewart,Basha,Bhatia,Ratajczyk,Martin,Craig,Kolasa,Bouska,Lanni,Harris,Malo,Carter,Bell
, p. 4768 - 4775 (2007/10/03)
Structure-activity optimization of inhibitory potency and duration of action of N-hydroxyurea containing 5-lipoxygenase inhibitors was conducted. The lipophilic heteroaryl template and the link group connecting the template to the N-hydroxyurea pharmacophore were modified. Inhibition of 5- lipoxygenase was evaluated in vitro in a human whole blood assay. An in vitro assay using liver microsomes from monkey was used to evaluate congeners for comparative rates of glucuronidation. (3-Heteroaryl-1-methyl-2-propynyl)-N- hydroxyureas were found to be more resistant to in vitro glucuronidation. The promising inhibitor N-[3-[5-(4-fluorophenoxy)-2-furyl]-1-methyl-2-propynyl]- N-hydroxyurea (6) was found to have stereoselective glucuronidation in monkey and man. The R enantiomer 7 provided longer duration of inhibition as evaluated by an ex vivo whole blood assay. Further optimization of the lipophilic template led to the discovery of (R)-(+)-N-[3-[5-[(4- fluorophenyl)methyl]-2-thienyl]-1-methyl-2-propynyl]-N-hydroxyurea (11) with more effective and prolonged inhibition of leukotriene biosynthesis than zileuton (1) and 7 in monkey and man. The optimized 5-lipoxygenase inhibitor 11 was selected for development as an investigational drug for leukotriene- mediated disorders.
