In vivo characterization of hydroxamic acid inhibitors of 5-lipoxygenase.
The hydroxamic acid functionally can be incorporated into simple molecules to produce potent inhibitors of 5-lipoxygenase. The ability of many of these hydroxamates to inhibit leukotriene synthesis in vivo has been measured directly with a rat peritoneal anaphylaxis model. Despite their potent enzyme inhibitory activity in vitro, many orally dosed hydroxamic acids only weakly inhibited leukotriene synthesis in vivo. This discrepancy is attributable at least in part to the rapid metabolism of hydroxamates to the corresponding carboxylic acids, which are inactive against the enzyme. A study of the structural features that affect this metabolism revealed that 2-arylpropionohydroxamic acids are relatively resistant to metabolic hydrolysis. Several members of this class of hydroxamates are described that are orally active inhibitors of leukotriene synthesis.
Summers
J B
JB
Department 47K, Abbott Laboratories, Abbott Park, Illinois 60064.
Gunn
B P
BP
Mazdiyasni
H
H
Goetze
A M
AM
Young
P R
PR
Bouska
J B
JB
Dyer
R D
RD
Brooks
D W
DW
Carter
G W
GW
D000284:Administration, Oral; D000818:Animals; D001091:Arachidonate Lipoxygenases / Q000037:antagonists & inhibitors*; D006877:Hydroxamic Acids / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D016859:Lipoxygenase Inhibitors; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013189:SRS-A / Q000096:biosynthesis; D013329:Structure-Activity Relationship
D006877:Hydroxamic Acids; D016859:Lipoxygenase Inhibitors; D013189:SRS-A; D001091:Arachidonate Lipoxygenases