Patrick R. Young

Inhibition of leukotriene biosynthesis in the rat peritoneal cavity.

In the search for a model of leukotriene (LT) production to provide a method to determine in vivo 5-lipoxygenase (5-LO) inhibitory activity by various compounds, a passive anaphylactic reaction in the rat peritoneal cavity was examined, refined and characterized. The reaction, produced by passive sensitization with an i.p. injection of rabbit anti-bovine serum albumin (anti-BSA) followed by an i.p. injection of BSA, resulted in the biosynthesis of large amounts of sulfidopeptide LTs measurable by immunoassay or by reversed phase high performance liquid chromatography. The oral activity of several 5-LO inhibitors has been examined using this model. An example of these is zileuton (Abbott-64077), a potent 5-lipoxygenase inhibitor now under clinical evaluation. Zileuton inhibited sulfidopeptide LT biosynthesis in the rat peritoneal cavity in a dose-dependent manner (ED50 = 3 mg/kg). WY-49,232, MK-866, BW A4C and phenidone also produced good activity with ED50 values of 6, 8, 11 and 17 mg/kg, respectively. This modified rat peritoneal anaphylaxis model appears to be a valuable tool for establishing in vivo activity of 5-LO inhibitors.

Pharmacological studies in the rat with [2-(2,3-didecanoyloxy)-propyl]2-acetyloxybenzoate (A-45474): An aspirin pro-drug with negligible gastric irritation

A triglyceride of aspirin, A-45474: [2-(1,3-didecanoyloxy)-propyl]2-acetyloxybenzoate, was developed to reduce the direct gastric irritant properties of aspirin. Studies in the rat show that oral administration of A-45474 produces anti-inflammatory activity comparable to aspirin with negligible gastric irritation. Compared with aspirin, plasma salicylate levels of A-45474 appeared less rapidly and were more sustained. It is concluded that incorporation of aspirin in the 2-position of a triglyceride bearing n-decanoyl groups in the 1- and 3-positions markedly reduces the gastric irritating properties of aspirin while maintaining its pharmacological effects.

O-alkylcarboxylate oxime and N-hydroxyurea analogs of substituted indole leukotriene biosynthesis inhibitors

Abstract Reference FLAP inhibitors 1 and 2 were converted into the corresponding O -acetic acid oxime congeners 8 and 11a , respectively, resulting in potent, orally active, leukotriene biosynthesis inhibitors. An attempt to create a dual FLAP and direct 5-LO inhibitor by replacing the carboxylate group in 1 with the N -hydroxyurea pharmacophore did not provide superior inhibitors.

Structure-activity relationships of the pyridazinone series of 5-lipoxygenase inhibitors

Abstract Structure activity analysis of the pyridazinone series as represented by the initial lead compound A-53612 revealed that the 1-phenyl-2H-tetrahydropyridazin-3-one structure was necessary for inhibitory activity as several modifications diverging from this structure led to a dramatic loss of inhibitory activity. Substituents on the phenyl ring had a marked effect on inhibitory activity and methemoglobinemia toxicity.

The properties of A-69412 : a small hydrophilic 5-lipoxygenase inhibitor

A compound which inhibits leukotriene biosynthesis could be clinically useful in treating several allergic and inflammatory diseases. One site for such inhibition is at the enzyme 5-lipoxygenase. Most inhibitors of this enzyme thus far described are poorly bioavailable. A-69412 is a small, relatively hydrophilic compound of theN-hydroxyurea class, which exhibits minimal plasma protein binding (6–12%). The compound was found to be a potent long-acting inhibitor of leukotriene formationin vivo in the rat (oral ED50=5 mg/kg) andex vivo in several species. In addition, the compound exhibits excellent bioavailability in dogs and monkeys with a relatively long elimination half-life in both the species (6 and 3 h, respectively). The biochemical activity and pharmacological profile of A-69412 indicates its potential utility in asthma and ulcerative colitis, and possibly other inflammatory and allergic conditions.

1-Phenyl-[2H]-tetrahydropyridazin-3-one, A-53612, a selective orally active 5-lipoxygenase inhibitor

Abstract Ring homologation of the known lipoxygenase inhibitor, phenidone to 1-phenyl-[2H]-tetrahydropyridazin-3-one provided A-53612, which was discovered to be a selective, orally active 5-lipoxygenase inhibitor. In contrast to phenidone, A-53612 did not cause significant inhibition of platelet 12-lipoxygenase, soybean 15-lipoxygenase, or intact rat PMNL cyclo-oxygenase at concentrations up to 100 μM.

Measurement of inflammatory reactions by a dye dilution method.

The rat pleural cavity has been shown to be useful for studying inflammatory reactions (Hurley & Spector 1965; Hurley et a1 1966; Di Rosa et a1 1971; Capasso et al 1975; Yamamoto et al 1975) and assessing the effects of anti-inflammatory agents (Sancilio 1969; Vinegar et al 1973; Tarayre et a1 1979). We describe a dye-dilution technique for measuring inflammatory reactions elicited in the rat pleural cavity. Exudate volume was determined from the decrease in absorbance of a dye solution placed in the cavity, thereby avoiding the need for quantitative sample recovery. Compared to a direct sampling technique, this method is more accurate and precise for quantitating both exudate volume and cellular influx. The simplicity and accuracy of the technique suggests its potential utility for other animal models requiring quantitation of body cavity fluid and cellular contents.

Structural analysis of 2-aryl-1,3-dione compounds as inhibitors of 5-lipoxygenase

Abstract The 2-phenylindane-1,3-dione system was observed to inhibit RBL-1 supernatant 5-lipoxygenase (5-LO) activity (IC50 = 15 μM). The structure-activity relationships for 5-LO inhibition were examined. Novel 2-phenylcycloheptan-1,3-diones and substituted 2-fluorophenylindane-1,3-dione inhibitors were prepared.