Studies on antiulcer drugs. 7. 2-Guanidino-4-pyridylthiazoles as histamine H2-receptor antagonists with potent gastroprotective effects against nonsteroidal antiinflammatory drug-induced injury.
A series of 2-guanidino-4-pyridylthiazole derivatives were synthesized and evaluated for anti-aspirin-ulcer, gastric antisecretory, and histamine-H2-receptor-antagonist activities. Several compounds showed superior anti-aspirin-ulcer activity to that of clinically used H2-antagonists in the rat. Among them, 4-[6-(acetamidomethyl)pyridin-2-yl]-2-guanidinothiazole (8) demonstrated potent inhibitory activities against gastric lesions caused by two kinds of nonsteroidal antiinflammatory drugs, aspirin and indomethacin, respectively, in addition to strong antisecretory activity. Compound 8 possessed a preventable ability for the aspirin-induced reduction of the gastric mucosal blood flow at an intragastric administration of 32 mg/kg in the rat. On the other hand, famotidine (32 mg/kg) exhibited no significant effect and ranitidine (100 mg/kg) aggravated the blood flow in this system.
Katsura
Y
Y
New Drug Research Laboratories, Fujisawa Pharmaceutical Company, Limited, Osaka, Japan.
Inoue
Y
Y
Tomishi
T
T
Ishikawa
H
H
Takasugi
H
H
D000818:Animals; D000897:Anti-Ulcer Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D001241:Aspirin; D001783:Blood Flow Velocity / Q000187:drug effects; D004285:Dogs; D005744:Gastric Acid / Q000378:metabolism; D005753:Gastric Mucosa / Q000098:blood supply; D006146:Guanidines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology; D006635:Histamine H2 Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D007213:Indomethacin; D008297:Male; D015394:Molecular Structure; D009200:Myocardial Contraction / Q000187:drug effects; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D013276:Stomach Ulcer / Q000139:chemically induced / Q000517:prevention & control*; D013844:Thiazoles / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use
D000897:Anti-Ulcer Agents; D006146:Guanidines; D006635:Histamine H2 Antagonists; D013844:Thiazoles; C085367:4-(6-(acetamidomethyl)pyridin-2-yl)-2-guanidinothiazole; D006632:Histamine; D001241:Aspirin; D007213:Indomethacin