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.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Cyclooxygenase Inhibitors/pharmacology , Dibenzoxepins/pharmacology , Hydroxamic Acids/pharmacology , Hydroxylamines/pharmacology , Lipoxygenase Inhibitors/pharmacology , 3T3 Cells , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Arachidonate 5-Lipoxygenase/metabolism , Arachidonic Acid/pharmacology , Cyclooxygenase Inhibitors/chemical synthesis , Cyclooxygenase Inhibitors/chemistry , Dibenzoxepins/chemical synthesis , Dibenzoxepins/chemistry , Dinoprostone/analysis , Hydroxamic Acids/chemical synthesis , Hydroxamic Acids/chemistry , Hydroxyeicosatetraenoic Acids/analysis , Hydroxylamines/chemical synthesis , Hydroxylamines/chemistry , Lipoxygenase Inhibitors/chemical synthesis , Lipoxygenase Inhibitors/chemistry , Mice , Molecular Structure , Structure-Activity RelationshipABSTRACT
A series of [(6,7-dichlorobenzo[b]thien-5-yl)oxy]acetic acids and their corresponding 1,1-dioxides were synthesized and evaluated for diuretic activity in the acute saline loaded mice (ASLM) and hypotensive activity in the spontaneously hypertensive rat (SHR). A significant number of compounds were found to display potent activity in one or both assays, and preliminary structure-activity relationships with respect to each assay were delineated. Compound 94, the 1,1-dioxide of [(6,7-dichloro-2-n-propylbenzo[b]thien-5-yl)oxy]acetic acid was markedly active in both the ASLM and SHR by oral administration. The combined diuretic/hypotensive profile of this compound was further substantiated by its good saluretic response in water loaded conscious dogs and a moderate to good activity in renal hypertensive rats and sinoaortic-deafferented hypertensive dogs.
Subject(s)
Antihypertensive Agents/chemical synthesis , Diuretics/chemical synthesis , Glycolates/chemical synthesis , Thiophenes/chemical synthesis , Acetates/chemical synthesis , Acetates/pharmacology , Animals , Antihypertensive Agents/pharmacology , Diuretics/pharmacology , Dogs , Female , Glycolates/pharmacology , Male , Mice , Rats , Rats, Inbred SHR , Rats, Inbred Strains , Structure-Activity Relationship , Thiophenes/pharmacologyABSTRACT
Several (3-aryl-2,3-dihydrobenzofuran-3-yl)alkanamines, designed as potential antidepressant agents with analgesic properties, were synthesized and pharmacologically evaluated. While two compounds (1a, 1f) displayed potent antitetrabenazine activity, concomitant antinociceptive activity in the phenylquinone writhing assay was not observed.
