title: Structure-activity relationships of N-hydroxyurea 5-lipoxygenase inhibitors.
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.
authors.affiliation: Immunoscience Research, Abbott Laboratories, Illinois 60064, USA.
authors.forename: A O
authors.initials: AO
authors.lastname: Stewart
authors.forename: P A
authors.initials: PA
authors.lastname: Bhatia
authors.forename: J G
authors.initials: JG
authors.lastname: Martin
authors.forename: J B
authors.initials: JB
authors.lastname: Summers
authors.forename: K E
authors.initials: KE
authors.lastname: Rodriques
authors.forename: M B
authors.initials: MB
authors.lastname: Martin
authors.forename: J H
authors.initials: JH
authors.lastname: Holms
authors.forename: J L
authors.initials: JL
authors.lastname: Moore
authors.forename: R A
authors.initials: RA
authors.lastname: Craig
authors.forename: T
authors.initials: T
authors.lastname: Kolasa
authors.forename: J D
authors.initials: JD
authors.lastname: Ratajczyk
authors.forename: H
authors.initials: H
authors.lastname: Mazdiyasni
authors.forename: F A
authors.initials: FA
authors.lastname: Kerdesky
authors.forename: S L
authors.initials: SL
authors.lastname: DeNinno
authors.forename: R G
authors.initials: RG
authors.lastname: Maki
authors.forename: J B
authors.initials: JB
authors.lastname: Bouska
authors.forename: P R
authors.initials: PR
authors.lastname: Young
authors.forename: C
authors.initials: C
authors.lastname: Lanni
authors.forename: R L
authors.initials: RL
authors.lastname: Bell
authors.forename: G W
authors.initials: GW
authors.lastname: Carter
authors.forename: C D
authors.initials: CD
authors.lastname: Brooks
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D005663:Furans; D005965:Glucuronates / Q000378:metabolism; D006801:Humans; D006918:Hydroxyurea / Q000031:analogs & derivatives*; D016859:Lipoxygenase Inhibitors; D008252:Macaca fascicularis; D008956:Models, Chemical; D051381:Rats; D013329:Structure-Activity Relationship; D013698:Templates, Genetic; D013876:Thiophenes
chemical_list: D004791:Enzyme Inhibitors; D005663:Furans; D005965:Glucuronates; D016859:Lipoxygenase Inhibitors; D013876:Thiophenes; D006918:Hydroxyurea