benzofurans and Peritonitis

Previous studies of experimental sepsis suggested that excessive systemic vasodilatation might be the stimulus to renal hypofiltration and fluid retention in sepsis. Successful therapy for this syndrome requires agents that either act to improve systemic haemodynamics without adverse renal effects, or that act directly on the kidney without impairing circulatory homeostasis. The plasma kallikrein-kinin system is a potent vasodilator pathway, activated by endotoxin. We studied the effect of aprotinin (Trasylol), which inhibits plasma kallikrein, in an ovine model of surgically-induced intra-abdominal sepsis. Given either as an early or late intervention, aprotinin was associated with increased mean arterial pressure and systemic vascular resistance, improved glomerular filtration rate, and increased urinary sodium excretion. In further studies, treatment with the thromboxane synthetase inhibitor, U63,557A (Upjohn), either before or after the surgical induction of peritonitis, was associated with increased glomerular filtration rate and sodium excretion, without any effect on systemic haemodynamics. Logical use of specific antagonists, based on an understanding of the pathophysiology of the septic ARF syndrome, is a desirable strategy.

Topics: Acute Kidney Injury; Animals; Aprotinin; Benzofurans; Glomerular Filtration Rate; Humans; Kallikrein-Kinin System; Natriuresis; Peritonitis; Sepsis; Sheep; Thromboxane-A Synthase

cis-4-(Piperazin-1-yl)-5,6,7a,8,9,10,11,11a-octahydrobenzofuro[2,3-h]quinazolin-2-amine, 4 (A-987306) is a new histamine H(4) antagonist. The compound is potent in H(4) receptor binding assays (rat H(4), K(i) = 3.4 nM, human H(4) K(i) = 5.8 nM) and demonstrated potent functional antagonism in vitro at human, rat, and mouse H(4) receptors in cell-based FLIPR assays. Compound 4 also demonstrated H(4) antagonism in vivo in mice, blocking H(4)-agonist induced scratch responses, and showed anti-inflammatory activity in mice in a peritonitis model. Most interesting was the high potency and efficacy of this compound in blocking pain responses, where it showed an ED(50) of 42 mumol/kg (ip) in a rat post-carrageenan thermal hyperalgesia model of inflammatory pain.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzofurans; Carrageenan; Disease Models, Animal; Drug Design; Drug Evaluation, Preclinical; Humans; Hyperalgesia; Ligands; Mice; Molecular Structure; Pain; Peritonitis; Quinazolines; Rats; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H4; Stereoisomerism; Structure-Activity Relationship

A series of 2-substituted benzofuran hydroxyamic acids were synthesized as rigid analogs of simple (benzyloxy)phenyl hydroxamates, evaluated for their in vitro and in vivo 5-lipoxygenase activity and found to be potent inhibitors of the enzyme. Substituents which enhanced lipophilicity near the 2-position of the benzofuran nucleus increased inhibitor potency but reduced oral activity. Incorporation of small polar substituents such as methoxymethylene, hydroxymethylene, and amino (urea) on the acyl group led to more consistent oral activity. The most potent inhibitors of this series in vitro were N-hydroxy-N-[1-(2-phenyl-5-benzofuranyl)-ethyl]furancarboxamide (12) and methyl 5-[N-hydroxy-N-[1-(2-(3,4,5-trimethoxyphenyl)-5-benzofuranyl]ethyl]-5- oxopentanoate (17), both with IC50 values of 40 nM, and in vivo the most potent compound was N-hydroxy-N-[1-(2-phenyl-5-benzofuranyl)ethyl]urea, 20, with an ED50 = 10.3 mg/kg.

Topics: Animals; Benzofurans; Lipoxygenase Inhibitors; Male; Mice; Molecular Structure; Peritonitis; Structure-Activity Relationship; Zymosan

A series of new 7-acyl substituted 1-benzoxepanes and 5-acyl substituted 2-methyl-1-benzoxolanes were synthesized and studied for anti-inflammatory properties. The benzoyl derivatives were more active than the corresponding halogenobenzoyl derivatives and previously reported structural analogues containing less methylene groups in their heterocyclic ring. The introduction of a methyl group at the 2-position of 5-cinnamoyl-1-benzoxolane heterocyclic ring significantly potentiated the activity. Anti-inflammatory and analgesic effects of 7-benzoyl-1-benzoxepane and 5-cinnamoyl-2-methyl-I-benzoxolane were less pronounced than those of indomethacin and diclofenac but greater than those of acetylsalicylic acid (ASA). Both compounds were less toxic and 5-cinnamoyl-2-methyl-1-benzoxolane was also less gastrotoxic than all the reference drugs mentioned above. Therapeutic indices of 5-cinnamoyl-2-methyl-1-benzoxolane were greater than those of diclofenac and significantly greater than those of ASA and indomethacin.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Experimental; Bentonite; Benzofurans; Benzoxepins; Carrageenan; Chemical Phenomena; Chemistry, Physical; Edema; Gastric Mucosa; Granuloma; Lethal Dose 50; Male; Mice; Mice, Inbred BALB C; Necrosis; Peritonitis; Rats; Rats, Wistar

To study the role of thromboxane in systemic sepsis and renal failure, peritonitis was induced surgically in 22 sheep, leading to local and systemic sepsis. A selective thromboxane synthetase inhibitor, U63,557A (Upjohn Co, Kalamazoo, MI) was given before surgery in five animals and 30 minutes after surgery in five animals. A typical picture of volume-loaded, normotensive, vasodilated septic shock developed in all animals. Twenty four hours after induction of sepsis, the control group showed a marked reduction in glomerular filtration rate (GFR), urine volume, and urinary sodium excretion. Pretreated animals showed no change in GFR and a smaller reduction in urine volume and sodium excretion. The posttreatment group showed no change in any parameters of renal function. Plasma renin activity, urinary TXB2 excretion, and urinary 6-keto PGF1 alpha excretion increased after 24 hours only in the control group. Urinary TXB2 excretion was reduced by 80% in animals given U63,557A before surgery. The results indicate a significant protective effect of U63,557A on renal function during septic shock, probably related to reduced thromboxane synthesis, with no apparent deleterious systemic effects. The results support a role for thromboxane in the pathogenesis of acute renal failure in systemic sepsis.

Topics: Animals; Benzofurans; Glomerular Filtration Rate; Kidney; Natriuresis; Peritonitis; Sheep; Shock, Septic; Thromboxane-A Synthase; Thromboxanes