title: Synthesis and antiulcer activity of novel 5-(2-ethenyl substituted)-3(2H)-furanones.
abstract: 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.
authors.affiliation: Wyeth-Ayerst Research, Princeton, New Jersey 08543-8000.
authors.forename: S W
authors.initials: SW
authors.lastname: Felman
authors.forename: I
authors.initials: I
authors.lastname: Jirkovsky
authors.forename: K A
authors.initials: KA
authors.lastname: Memoli
authors.forename: L
authors.initials: L
authors.lastname: Borella
authors.forename: C
authors.initials: C
authors.lastname: Wells
authors.forename: J
authors.initials: J
authors.lastname: Russell
authors.forename: J
authors.initials: J
authors.lastname: Ward
mesh_terms: D000818:Animals; D000897:Anti-Ulcer Agents / Q000138:chemical synthesis* / Q000627:therapeutic use*; D001241:Aspirin; D001572:Benzofurans / Q000737:chemistry* / Q000627:therapeutic use; D000431:Ethanol; D005663:Furans / Q000138:chemical synthesis* / Q000627:therapeutic use*; D007213:Indomethacin; D008297:Male; D015394:Molecular Structure; D051381:Rats; D011919:Rats, Inbred Strains; D013276:Stomach Ulcer / Q000139:chemically induced / Q000188:drug therapy*; D013329:Structure-Activity Relationship
chemical_list: D000897:Anti-Ulcer Agents; D001572:Benzofurans; D005663:Furans; D000431:Ethanol; C045902:spizofurone; D001241:Aspirin; D007213:Indomethacin