Dibenzoxepinone hydroxylamines and hydroxamic acids: dual inhibitors of cyclooxygenase and 5-lipoxygenase with potent topical antiinflammatory activity.
Hydroxylamine and hydroxamic acid derivatives of a known nonsteroidal antiinflammatory dibenzoxepine series display both cyclooxygenase (CO) and 5-lipoxygenase (5-LO) inhibitory properties. Many of these new dual CO/5-LO inhibitors also exhibit potent topical antiinflammatory activity in the arachidonic acid-induced murine ear edema model. On the basis of their promising profile of in vitro and in vivo activities, hydroxamic acids 24h, 3-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)-N-hydroxy-N-++ +methylpropanamide (HP 977), and 25, 3-(6,11-dihydrodibenz[b,e]oxepin-2-yl)-N-hydroxy-N- methylpropanamide (P10294), were selected as developmental candidates for the topical treatment of inflammatory skin disorders.
Hamer
R R
RR
Hoechst-Roussel Pharmaceuticals Inc., Somerville, New Jersey 08876, USA.
Tegeler
J J
JJ
Kurtz
E S
ES
Allen
R C
RC
Bailey
S C
SC
Elliott
M E
ME
Hellyer
L
L
Helsley
G C
GC
Przekop
P
P
Freed
B S
BS
White
J
J
Martin
L L
LL
D016475:3T3 Cells; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D016718:Arachidonic Acid / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D003990:Dibenzoxepins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015232:Dinoprostone / Q000032:analysis; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006893:Hydroxyeicosatetraenoic Acids / Q000032:analysis; D006898:Hydroxylamines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D015394:Molecular Structure; D013329:Structure-Activity Relationship
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D003990:Dibenzoxepins; C097779:HP 977; D006877:Hydroxamic Acids; D006893:Hydroxyeicosatetraenoic Acids; D006898:Hydroxylamines; D016859:Lipoxygenase Inhibitors; C097780:P 10294; D016718:Arachidonic Acid; C022022:5-hydroxy-6,8,11,14-eicosatetraenoic acid; D001094:Arachidonate 5-Lipoxygenase; D015232:Dinoprostone