Author: Ushiro, Toshihisa ; Yamazaki, Takashi ; Ichihara, Toshio ; Narita, Mitsuhiro ; Tsukimi, Yasuhiro ; Nishigaito, Toshiki ; Banno, Kimiko ; Ishikawa, Harumi ; Hirase, Jyoji ; Tanaka, Hironori

3-Amino-5-methyl-2(2-methyl-3-thienyl)- imidazo[1,2-a]thieno[3,2-c]pyridine, SPI-447, is a potent gastric H+,K(+)-ATPase inhibitor, but a detailed mechanism of the inhibition is unknown. This study was designed to investigate the mechanism by which SPI-447 inhibits gastric H+,K(+)-ATPase. For this purpose, the inhibitory action of SPI-447 on gastric H+,K(+)-ATPase from porcine gastric mucosa was compared with that of omeprazole (an irreversible inhibitor) and SCH28080 (a reversible inhibitor). All compounds produced dose-dependent inhibition of gastric H+,K(+)-ATPase, and the inhibitory intensities were increased under acidic conditions. The anti-H+,K(+)-ATPase actions of SPI-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(+)-ATPase-mediated H(+)-transport by SPI-447 and SCH28080, but had no effect on that by omeprazole. The anti-gastric H+,K(+)-ATPase action of SPI-447 was additive with that of SCH28080. SPI-447 and SCH28080 had no effect on Na+,K(+)-ATPase activity. These findings indicated that the inhibitory mechanism of SPI-447 on gastric H+,K(+)-ATPase was similar to that of SCH28080, but different from that of omeprazole; i.e., 1) reversible, 2) SH-group independent, 3) K(+)-competitive, and 4) highly specific against gastric H+,K(+)-ATPase.

01 Jan 1997·Japanese Journal of Pharmacology

Inhibition of Gastric H+,K+-ATPase by 3-Amino-5-methyl-2-(2-methyl-3-thienyl)imidazo[1,2-α]thieno[3,2-c]pyridine, SPI-447

Article

Author: Tsukimi, Yasuhiro ; Ushiro, Toshihisa ; Tanaka, Hironori

We investigated the effect of a newly synthesized compound, 3-amino-5-methyl-2-(2-methyl-3-thienyl)imidazo[1,2-a]thieno[3,2-c]pyridi ne (SPI-447), on the activity of H+,K+-ATPase isolated from porcine gastric mucosa. In lyophilized gastric vesicles, SPI-447 inhibited K+-stimulated ATPase activity in a dose-dependent manner in a pH 7.4 solution (IC50=4.2 microM (1.05-16.8)). The inhibitory action of SPI-447 was enhanced at pH 6.8 (IC50=1.05 microM (0.31-3.57)) and not influenced by glutathione. In intact gastric vesicles, SPI-447 had no effect on the spontaneous diffusion of H+ across the microsomal membrane. These results indicate that SPI-447 directly inhibits gastric H+,K+-ATPase activity in a SH group-independent manner.

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Indication	Highest Phase	Country/Location	Organization	Date
Stomach Ulcer	Phase 3	JP	Shin Nippon Biomedical Laboratories, Ltd.	-

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