Yasuhiro Tsukimi, Toshihisa Ushiro, Takashi Yamazaki, Harumi Ishikawa,
Jyoji Hirase,
Mitsuhiro Narita, Toshiki Nishigaito, Kimiko Banno, Toshio Ichihara and
Hironori Tanaka
Department of New Drug Research Laboratories, Technical Headquarters,
Shinnippon Pharmaceutical, Inc.,
370 Mita, Kishiwada 596ﾐ0808, Japan
Abstract: 3ﾐAminoﾐ5ﾐmethylﾐ2(2ﾐmethylﾐ3ﾐthienyl)ﾐimidazo[1,2ﾐa]thieno[3,2ﾐc]pyridine,
SPIﾐ447, is a potent gastric H+,K+ﾐATPase inhibitor,
but a detailed mechanism of the inhibition is unknown. This study was designed
to investigate the mechanism by which SPIﾐ447 inhibits gastric H+,K+ﾐATPase.
For this purpose, the inhibitory action of SPIﾐ447 on gastric H+,K+ﾐATPase
from porcine gastric mucosa was compared with that of omeprazole (an irreversible
inhibitor) and SCH28080 (a reversible inhibitor). All compounds produced
doseﾐdependent inhibition of gastric H+,K+ﾐATPase,
and the inhibitory intensities were increased under acidic conditions. The
antiﾐH+,K+ﾐATPase actions of SPIﾐ447 and SCH28080
were attenuated by dilution, but not influenced by glutathione pretreatment.
In contrast, that of omeprazole was not influenced by dilution, but was
suppressed by glutathione pretreatment. KCl addition reversed the inhibition
of H+,K+ﾐATPaseﾐmediated H+ﾐtransport by
SPIﾐ447 and SCH28080, but had no effect on that by omeprazole. The antiﾐgastric
H+,K+ﾐATPase action of SPIﾐ447 was additive with that
of SCH28080. SPIﾐ447 and SCH28080 had no effect on Na+,K+ﾐATPase
activity. These findings indicated that the inhibitory mechanism of SPIﾐ447
on gastric H+,K+ﾐATPase was similar to that of SCH28080,
but different from that of omeprazole; i.e., 1) reversible, 2) SHﾐgroup
independent, 3) K+ﾐcompetitive, and 4) highly specific against
gastric H+,K+ﾐATPase.
Keywords: H+,K+ﾐATPase inhibitor, Antiﾐulcer drug,
SPIﾐ447, Omeprazole, SCH28080