Byciclic compounds with potential antiulcer and/or antisecretory activity. III--2-substituted tetrahydrothiazolo-[5,4-c]pyridines.
As the ultimate result of a long-term search for new bicyclic molecules potentially endowed with antiulcer and/or antisecretory activity, simple urea derivatives of 2-guanidino-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine [(VIII), Fig. 1; X = 0, R = alkyl], displaying a strong inhibition of stress- and ASA-induced gastric ulcers and of basal gastric secretion, were found. Their potency does compare very favourably with that of cimetidine and ranitidine and approaches that of famotidine. On spontaneously beating guinea pig atria they behaved as inhibitors of the histamine H2-receptor. In contrast with cimetidine and ranitidine but like other recently described inhibitors (famotidine included), the most active compounds (VIII) caused a surmountable antagonism only at low concentrations and an unsurmountable antagonism at higher concentrations. The onset of action was slow, while the inhibitory effect was hardly reversed by washing. The rational development of the research and the synthetic approach, as well as a quantitative assessment of both in vitro and in vivo potencies in comparison with the best known, clinically used drugs, are shown in detail.
Scarponi
U
U
Chemical Research and Development, Farmitalia Carlo Erba Spa, Milano, Italy.
Lazzarini
A M
AM
Caprioli
R
R
de Castiglione
R
R
Toti
D
D
Vaghi
F
F
Castello
R
R
Ceserani
R
R
D000818:Animals; D000897:Anti-Ulcer Agents / Q000138:chemical synthesis*; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D001952:Bridged-Ring Compounds / Q000138:chemical synthesis*; D055598:Chemical Phenomena; D002621:Chemistry; D005744:Gastric Acid / Q000378:metabolism; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006635:Histamine H2 Antagonists / Q000138:chemical synthesis; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009130:Muscle, Smooth / Q000187:drug effects; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D051381:Rats; D011919:Rats, Inbred Strains; D013844:Thiazoles / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity
D000897:Anti-Ulcer Agents; D001643:Bridged Bicyclo Compounds; D001952:Bridged-Ring Compounds; D006635:Histamine H2 Antagonists; D011725:Pyridines; D013844:Thiazoles