A newly synthesized pyridine derivative, (Z)-5-methyl-2-[2-(1-naphthyl)ethenyl]-4-piperidinopyridine hydrochloride (AU-1421), as a reversible gastric proton pump inhibitor.
A newly synthesized pyridine derivative, (Z)-5-methyl-2-[2-(1-naphthyl)ethenyl]-4-piperidinopyridine hydrochloride (AU-1421), was found to inhibit the gastric proton pump in vitro and in vivo. In the leaky membrane vesicles of hog gastric mucosa, AU-1421 inhibited the K(+)-stimulated H, K-ATPase activity competitively with respect to K+, with a Ki value of 0.18 microM at pH 7.4 and 0.10 microM at pH 6.4. This inhibition was not affected by the length of the preincubation time of the enzyme with AU-1421, and activity was restored by dialysis. In the intact hog gastric membrane vesicles, which developed a pH gradient in the presence of valinomycin, AU-1421 also inhibited the gastric proton pump activity as measured by the quench of acridine orange fluorescence. In the isolated rabbit gastric glands, AU-1421 inhibited the histamine-, dibutyryl cAMP- and K(+)-stimulated uptake of [14C]aminopyrine into gastric glands with similar IC50 values of about 1 microM. Furthermore, AU-1421 suppressed gastric acid secretion in acute fistula rats and Heidenhain-pouch dogs with the same potency as cimetidine. These results suggest that AU-1421 is an antisecretory agent which reversibly inhibits the H,K-ATPase.
Hioki
Y
Y
Central Research Laboratories, Banyu Pharmaceutical Co., Ltd., Tokyo, Japan.
Takada
J
J
Hidaka
Y
Y
Takeshita
H
H
Hosoi
M
M
Yano
M
M
D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000632:Aminopyrine / Q000378:metabolism; D000818:Animals; D002927:Cimetidine / Q000494:pharmacology; D004285:Dogs; D005753:Gastric Mucosa / Q000187:drug effects / Q000201:enzymology; D005755:Gastrins / Q000494:pharmacology; D005768:Gastrointestinal Hormones / Q000037:antagonists & inhibitors*; D017506:H(+)-K(+)-Exchanging ATPase; D066298:In Vitro Techniques; D008297:Male; D009281:Naphthalenes / Q000494:pharmacology*; D011506:Proteins / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D013552:Swine
D005755:Gastrins; D005768:Gastrointestinal Hormones; D009281:Naphthalenes; D011506:Proteins; D011725:Pyridines; C052257:hydrogen potassium ATPase, gastric endogenous activator protein, mammal; D000632:Aminopyrine; C063370:AU 1421; D002927:Cimetidine; D000251:Adenosine Triphosphatases; D017506:H(+)-K(+)-Exchanging ATPase