Dibenzoxepinone Hydroxylamines and Hydroxamic Acids:  Dual Inhibitors of Cyclooxygenase and 5-Lipoxygenase with Potent Topical Antiinflammatory Activity

Abstract

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.

Amidases: versatile enzymes in nature

“…-Anti-inflammatory -To treat chronic asthma Hamer et al (1996) α-aminohydroxamic acid t n e g a V I H -i t n A Gao et al (1995) Desferrioxamine B Antimalarial Tsafack et al (1995) Cyclic hydroxamic acids 2,4-dihydroxy-1,4-benzoxazin-3-one (DIBOA) 2,4-dihydroxy-7-methoxy-1,4-benzoxazin-3-one (DIMBOA) -Provide resistance against pathogen and insects Givovich et al (1995); Nakagava et al…”

Identification of 4-[4-(4-Fluoro-Phenyl)-Thiazol-2-Ylamino]-2,6-Dimethyl-Phenol (KR-33749) as an Inhibitor of 5-Lipoxygenase with Potent Antiinflammatory Activity

“…IgE levels were monitored from sera at the indicated times ( c ). inhibitors of cyclooxygenase and 5-LO were reported to exhibit potent antiinflammatory activity in an arachidonic acid-induced murine ear edema model [24] . On the other hand, selective cyclooxygenase-2 inhibitors were withdrawn from the market due to the side effects of heart attack and adverse skin reaction [25] .…”

An improved bioprocess for synthesis of acetohydroxamic acid using DTT (dithiothreitol) treated resting cells of Bacillus sp. APB-6

“…have also been investigated as anti-human immunodeficiency virus agents, antimalarial agents and have also been recommended for treatment of ureaplasma infections and anaemia (Gao et al, 1995;Holmes, 1996). Some fatty hydroxamic acids have been studied as inhibitors of cyclooxygenase and 5-lipooxygenase with a potent antiinflammatory activity (Hamer et al, 1996).…”