- Process for the preparation of arylalkynyl-N-hydroxyurea derivatives having lipoxygenase inhibitory activity
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The present invention provides a process for the preparation of a compound of formula STR1 wherein R is a straight or branched alkyl group of from one to twelve carbon atoms; M represents hydrogen or a pharmaceutically acceptable cation; and A is selected from optionally substituted carbocyclic phenyl.
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- Structure-activity relationships of N-hydroxyurea 5-lipoxygenase inhibitors
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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.
- 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.
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p. 1955 - 1968
(2007/10/03)
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- ACETYLENE DERIVATIVES HAVING LIPOXYGENASE INHIBITORY ACTIVITY
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Compounds of the structure where p and q are zero or one, but cannot both be the same, M is a pharmaceutically acceptable cation or a metabolically cleavable group, B is a valence bond or a straight or branched alkylene group, R is alkyl, cycloalkyl or --NR1 R2, where R1 and R2 are hydrogen, alkyl, cycloalkyl or alkanoyl, and A is optionally substituted carbocyclic aryl, furyl, benzo[b]furyl, thienyl, or benzo[b]thienyl are potent inhibitors of lipoxygenase enzymes and thus inhibit the biosynthesis of leukotrienes. These compounds are useful in the treatment or amelioration of allergic and inflammatory disease states.
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