Antiulcer agents. 5. Inhibition of gastric H+/K(+)-ATPase by substituted imidazo[1,2-a]pyridines and related analogues and its implication in modeling the high affinity potassium ion binding site of the gastric proton pump enzyme.
A number of substituted imidazo[1,2-a]pyridines and related analogues were selected for biochemical characterization in vitro against both the purified gastric proton pump enzyme, H+/K(+)-ATPase, and the intact gastric gland. The inhibitory activity in these two in vitro models was then examined for correlation with the gastric antisecretory potency determined for these compounds in vivo by using the histamine-stimulated Heidenhain pouch dog. Analysis of the biological data suggested that the inhibitory activity of the analogues determined in two in vitro models is predictive of their in vivo gastric antisecretory activity following intravenous, but not oral, administration. Furthermore, the good correlation observed between the in vitro and in vivo models suggests that these compounds are gastric proton pump inhibitors in vivo. A molecular modeling study of these compounds using the active analogue approach has defined the molecular volume which is shared by the active analogues, as well as the molecular volume which is common to the inactive analogues. Graphical representation of the difference between these molecular volumes can be interpreted in terms of a hypothetical description of the pharmacophore by means of which 3-(cyanomethyl)-2-methyl-8-(phenylmethoxy)imidazo[1,2-a]pyridine, Sch 28080 (1) and its analogues interact with the gastric proton pump enzyme, H+/K(+)-ATPase.
Kaminski
J J
JJ
Department of Chemical Research, Schering-Plough Research, Schering-Plough Corporation, Bloomfield, New Jersey 07003.
Wallmark
B
B
Briving
C
C
Andersson
B M
BM
D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors*; D000818:Animals; D000897:Anti-Ulcer Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001665:Binding Sites; D055598:Chemical Phenomena; D002621:Chemistry; D004285:Dogs; D005753:Gastric Mucosa / Q000187:drug effects; D017506:H(+)-K(+)-Exchanging ATPase; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D008958:Models, Molecular; D011188:Potassium / Q000378:metabolism; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology; D011817:Rabbits; D013329:Structure-Activity Relationship; D013552:Swine
D000897:Anti-Ulcer Agents; D007093:Imidazoles; D011725:Pyridines; D000251:Adenosine Triphosphatases; D017506:H(+)-K(+)-Exchanging ATPase; D011188:Potassium