benzofurans and spizofurone

In order to investigate new antiulcer agents, spizofurone 1 (AG-629) was fragmented and reassembled to generate 5-phenyl-2,2-dimethyl-3(2H)-furanone (bullatenone, 2). Because of the antiulcer activity of 2,5-phenyl-substituted 2,2-dimethyl-3(2H)-furanones (3-6) were made and shown to have poor activity. Insertion of an ethenyl link between the furanone and phenyl rings gave 5-(2-phenylethenyl)-2,2-dimethyl-3(2H)- furanone (7). This compound had better activity than 2. Compounds 8-41 were synthesized to evaluate the SAR in 5-(2-ethenyl substituted)-3(2H)-furanones. Electron-withdrawing substituents on the aromatic ring (8, 10, 19, and 20) gave 2-3-fold higher activity. Further increases in the activity were found when the phenyl ring was replaced by heterocyclic nuclei. Compounds that contained a thiophene (29), pyridine (24-26), or quinoline ring (32) had the best activity. Replacement of the methyl group on the furanone ring with a phenyl (34) or p-fluorophenyl (40) substituent in the 2-pyridine series gave compounds with activity that ranked with the best obtained in this study. The best compounds from the above SAR studies were evaluated in the ethanol-necrosis model for duration of cytoprotection action. Compounds 19, 24, and 29, which had the best duration of action, were tested with AG-629 in the acidified aspirin and indomethacin-induced lesion models. Only compound 24 had equivalent activity with AG-629 in both models.

Topics: Animals; Anti-Ulcer Agents; Aspirin; Benzofurans; Ethanol; Furans; Indomethacin; Male; Molecular Structure; Rats; Rats, Inbred Strains; Stomach Ulcer; Structure-Activity Relationship

The effect of a methanol extract of Sophora flavescens root was examined on gastric ulcers induced in rats by HCl/ethanol in order to substantiate its reputed protective properties. Oral doses of 1 g/kg completely suppressed ulceration. Results suggest that oral administration of 50 mg/kg of vexibinol, a flavanol found in the extract, inhibited ulceration more effectively than spizofurone at 100 mg/kg.

Topics: Animals; Anti-Ulcer Agents; Benzofurans; Ethanol; Flavanones; Flavonoids; Male; Methanol; Plant Extracts; Plants, Medicinal; Rats; Rats, Inbred Strains; Stomach Ulcer

The effect of spizofurone, a new anti-ulcer agent, on alkaline secretion was studied in an isolated sheet of bullfrog (10(-4)-10(-3) M) as well as prostaglandin E2 (PGE2, 10(-8)-10(-5) M) added to the nutrient solution increased alkaline secretion, transmucosal potential difference (PD) and short-circuit current (Isc), in a concentration-dependent manner. The maximum increases in alkaline secretion stimulated by spizofurone and PGE2 were much the same. Spizofurone also showed this effect when added to the secretory solution while PGE2 did not. Treatment with indomethacin partly but significantly inhibited the effect of spizofurone, but did not affect that of PGE2. These results indicate that the increase in alkaline secretion in bullfrog duodenal mucosa seen in the presence of spizofurone is mediated, at least in part, by stimulation of endogenous PGs synthesis.

Topics: 1-Methyl-3-isobutylxanthine; Animals; Anti-Ulcer Agents; Benzofurans; Dinoprostone; Duodenum; Female; Hydrogen-Ion Concentration; In Vitro Techniques; Indomethacin; Intestinal Mucosa; Male; Prostaglandins E; Rana catesbeiana

The effect of spizofurone (AG-629), a new anti-ulcer agent, on gastric mucosal blood flow was investigated in anesthetized dogs and the effects were compared with those of prostaglandin E2. Intravenous administration of spizofurone in doses of 15 and 30 mg/kg caused a dose-related increase in gastric mucosal blood flow. Spizofurone (1-10 mg/ml) given intragastrically for 15 min produced a sustained increase in gastric mucosal blood flow in a concentration-dependent manner; with 3 mg/ml there was about a 50% increase in gastric mucosal blood flow at the peak and a 2 h duration of action. The mode of action of spizofurone was similar to that of prostaglandin E2. The reduction in the gastric mucosal blood flow as induced by indomethacin was markedly improved by spizofurone. The topical action of spizofurone was confirmed in an in situ experiment using a stomach flap fixed to a lucite chamber. These results indicate that spizofurone increases gastric mucosal blood flow after systemic and topical administration, and this increase in gastric mucosal blood flow would account for the anti-ulcer effects of this drug.

Topics: Aminopyrine; Animals; Anti-Ulcer Agents; Benzofurans; Dinoprost; Dinoprostone; Dogs; Female; Gastric Mucosa; Hydrogen; In Vitro Techniques; Indomethacin; Isoproterenol; Male; Prostaglandins E; Prostaglandins F; Regional Blood Flow; Time Factors

The protective effect of spizofurone (AG-629) on the rat gastric mucosa was studied in the presence of various stimuli. Spizofurone given orally markedly inhibited gastric lesions induced by ethanol (ED50 = 6.5 mg/kg). Spizofurone inhibited ethanol-induced gastric lesions even when administered intraperitoneally (i.p.), but the onset of action after oral administration was shorter. Spizofurone given orally or i.p. in a dose range of 25-200 mg/kg inhibited indomethacin-induced gastric antral ulcers in re-fed rats. Furthermore, spizofurone potentiated the inhibitory effect of prostaglandin E2 on indomethacin-induced gastric antral ulcers. Spizofurone given i.p. prevented a decrease in potential difference and the formation of gastric lesions induced by intragastric instillation of 30 mM aspirin in 0.1 N HCl. Spizofurone given i.p. inhibited the increase in net fluxes of H+ and Na+ caused by intragastric instillation of 15% ethanol in 0.1 N HCl. These findings indicate that spizofurone, like prostaglandin E2, exerts gastric mucosal protection and even potentiates the anti-ulcer effect of prostaglandin E2. The gastric mucosal protection by spizofurone is ascribed in part to preservation of the mucosal barrier.

Topics: Animals; Anti-Ulcer Agents; Aspirin; Benzofurans; Dinoprostone; Electrolytes; Ethanol; Gastric Mucosa; Indomethacin; Male; Prostaglandins E; Rats; Rats, Inbred Strains; Stomach Ulcer

The effects of 5-acetylspiro[benzofuran-2(3H),1'-cyclopropan]-3-one (AG 629), a newly synthesized compound, on various experimentally induced ulcers were investigated. Oral or intraduodenal administration of AG 629 in a dose range of 25-100 mg/kg inhibited water-immersion stress ulcer, exertion ulcer, Shay ulcer, indometacin- and acetylsalicylic acid (ASA)-induced gastric ulcer, and indomethacin-induced small intestinal ulcer in rats, histamine-induced gastric ulcer in guinea pigs, and ASA-induced gastric ulcer in dogs, though it was not effective against cysteamine-induced duodenal ulcer in rats. AG 629 in doses of 6.3-25 mg/kg p.o. twice a day significantly promoted the healing of acetic acid- or thermal-cortisone-induced gastric ulcers and acetic acid-induced duodenal ulcers in rats. AG 629 (25-100 mg/kg i.d.) inhibited the secretion of gastric acid and pepsin in pylorus-ligated rats and the acid secretion stimulated by distension of the rat stomach with air, whereas this compound did not affect acid secretion stimulated by histamine, pentagastrin, carbachol or 2-deoxy-D-glucose. This study shows that AG 629 has both prophylactic and curative effects on various ulcers. The anti-ulcer effect of this agent seems to be mediated primarily by increasing mucosal resistance and secondarily by an antisecretory activity.

Topics: Acetates; Acetic Acid; Acute Disease; Animals; Anti-Ulcer Agents; Aspirin; Benzofurans; Chronic Disease; Cysteamine; Dogs; Duodenal Ulcer; Female; Gastric Acid; Guinea Pigs; Histamine; Hot Temperature; Indomethacin; Male; Physical Exertion; Rats; Rats, Inbred Strains; Stomach Ulcer; Stress, Psychological