Structure-activity relationships of N-hydroxyurea 5-lipoxygenase inhibitors.
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.
Stewart
A O
AO
Immunoscience Research, Abbott Laboratories, Illinois 60064, USA.
Bhatia
P A
PA
Martin
J G
JG
Summers
J B
JB
Rodriques
K E
KE
Martin
M B
MB
Holms
J H
JH
Moore
J L
JL
Craig
R A
RA
Kolasa
T
T
Ratajczyk
J D
JD
Mazdiyasni
H
H
Kerdesky
F A
FA
DeNinno
S L
SL
Maki
R G
RG
Bouska
J B
JB
Young
P R
PR
Lanni
C
C
Bell
R L
RL
Carter
G W
GW
Brooks
C D
CD
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
D004791:Enzyme Inhibitors; D005663:Furans; D005965:Glucuronates; D016859:Lipoxygenase Inhibitors; D013876:Thiophenes; D006918:Hydroxyurea