A series of new 2-(2,3-dihydro-2-oxo-l,3,4-oxadiazol-5-yl) benzo heterocycles has been prepared. These compounds were tested as inhibitors of antigen-induced release of histamine (AIR) in vitro from rat peritoneal mast cells (RMC) and as inhibitors of IgE-mediated rat passive cutaneous anaphylaxis in the rat (PCA). Most of this new class of antiallergic agents showed good activity in the RMC assay. The most potent compound, 3-chloro-2-(2,3-dihydro-2-oxo-l,3,4-oxadiazol-5-yl)benzo[b]thiophene (6t), with an 1® value of 0.2 µ , is 15 times more potent than disódium cromoglycate (DSCG) in the RMC assay. Many compounds were orally active in the PCA test, and several of these compounds showed higher potency when given in this way to that shown by DSCG when given intraperitoneally.Since the introduction of disodium cromoglycate (DSCG, 1) for the treatment of asthma and allergy disease/ nui i merous compounds have been reported to be orally active antiallergic agents.1 2 Most of these compounds are carboxylic acids or derivatives thereof, such as esters3 or tetrazoles.4 There are, however, several exceptions, such as nivimedone (2),5 the pyran enamines 3,6 the tetracyclic pyrazole 4,7 and the benzoxepines 5.8 are able to determine, the benzo heterocyclic oxadiazolones (6) are new.14

Summary Extracts of the creosote bush (Larrea tridentata, family Zygophyllaceae) have long been used as a folk remedy for Type II (non-insulin-dependent) diabetes by native Americans in southwestern North America. In this study we have evaluated the metabolic effects of masoprocol, a pure compound isolated from the creosote bush, in a rat model of Type II diabetes. Animals were fed a 20 % fat (by weight) diet for 2 weeks prior to intravenous injection with streptozotocin (STZ, 0.19 mmol/kg). Diabetic animals (glucose 16±33 mmol/l) were treated with vehicle, metformin (0.83 mmol/kg body weight) or masoprocol (0.83 mmol/kg body weight) twice a day for 4 days. Masoprocol treatment lowered glucose concentrations an average of 35 % compared with vehicle (14.2 ± 1.1 vs 21.7 ± 1.0 mmol/l, p < 0.001), a reduction similar to metformin treatment (12.8 ± 0.9 mmol/l), without any change in insulin concentration. Masoprocol treatment also lowered triglyceride concentrations 80 % compared with vehicle (1.0 ± 0.1 vs 4.8 ± 0.3 mmol/l, p < 0.001), a reduction far greater than following metformin treatment (3.6 ± 0.3 mmol/l). Non-esterified fatty acid and glycerol concentration were decreased by approximately 65 % by masoprocol compared with vehicle, a reduction approximately twice as great as seen with metformin (p < 0.001). The effect of masoprocol on in vivo insulin-mediated glucose disposal was evaluated by infusing fat-fed/STZ rats with glucose (0.22 mmol × kg × min ±1 ) and insulin (30 pmol × kg × min ±1 ) for 5 h. In response to the infusion, steadystate plasma glucose concentrations were reduced 30 % in masoprocol-treated animals compared with vehicle controls (p < 0.05) with no change noted in rats treated with metformin. The effect of masoprocol treatment was also tested in primary adipocytes isolated from normal animals. Adipocytes treated with masoprocol (30 mmol/l) had higher basal and insulin-stimulated glucose clearance than did adipocytes treated with vehicle (p < 0.05). These data show that masoprocol decreases both plasma glucose and triglyceride concentrations in fat-fed/STZ rats, presumably as a result of its ability to both increase glucose disposal and decrease lipolysis. [Diabetologia (1999) 42: 102±106]

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SP-303 is safe and well tolerated. These results suggest that SP-303 may be effective in reducing stool weight and frequency in patients with AIDS and diarrhea.

A series of new substituted arylmethyl phenyl ethers has been prepared. These compounds were tested as inhibitors of 5-lipoxygenase (5-LO) in rat neutrophils, in vitro antagonists of leukotriene-induced contraction of guinea pig (GP) lung parenchymal strips, and inhibitors of slow reacting substance of anaphylaxis (SRS-A) mediated bronchospasm in the GP in vivo. Most representatives of this new class of potential antiallergic/antiinflammatory agents showed potent inhibition of 5-LO activity in rat PMNs. The most potent compound, 2-[[3-(1-hydroxyhexyl)phenoxy]-methyl]quinoline (33), had an I50 of 0.12 microM in the rat PMN 5-LO assay and an I50 of 3.6 microM in the leukotriene-induced contraction of GP lung parenchymal strips, and it also showed 91% inhibition of SRS-A-mediated bronchospasm in the GP in vivo at 10 mg/kg, administered intraduodenally. Some of the compounds in this series were also leukotriene antagonists in vitro, and several of them showed in vivo activity against SRS-A-mediated bronchospasm in the GP.