Differential effects of a series of hydroxamic acid derivatives on 5-lipoxygenase and cyclooxygenase from neutrophils and 12-lipoxygenase from platelets and their in vivo effects on inflammation and anaphylaxis.
The synthesis of a series of novel substituted hydroxamates has been described along with their profile of inhibitory activity against 5-lipoxygenase, 12-lipoxygenase, and cyclooxygenase enzymes. The structure--activity relationship suggests that future molecules could be designed to specifically inhibit one or more of these enzymes since there were definite differences in structure--activity relationships for these different enzymes. A representative number of these compounds have been tested in vivo and found to possess potent oral activity in a systemic anaphylaxis model mediated by leukotrienes and topical activity in an arachidonic acid induced inflammation model. One of these molecules, compound 20, demonstrated that a leukotriene antagonist pharmacophore can be modified such that it contains both antagonist activity and 5-lipoxygenase inhibitory activity.
Huang
F C
FC
Rorer Central Research, Horsham, Pennsylvania 19044.
Shoupe
T S
TS
Lin
C J
CJ
Lee
T D
TD
Chan
W K
WK
Tan
J
J
Schnapper
M
M
Suh
J T
JT
Gordon
R J
RJ
Sonnino
P A
PA
D000707:Anaphylaxis / Q000517:prevention & control*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis*; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology; D055598:Chemical Phenomena; D002621:Chemistry; D016861:Cyclooxygenase Inhibitors; D006168:Guinea Pigs; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D066298:In Vitro Techniques; D020024:Leukotriene Antagonists; D016859:Lipoxygenase Inhibitors; D008297:Male; D051379:Mice; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology; D051381:Rats; D011919:Rats, Inbred Strains
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D006877:Hydroxamic Acids; D020024:Leukotriene Antagonists; D016859:Lipoxygenase Inhibitors