BIOCHEMICAL AND PHARMACOLOGICAL PROPERTIES OF A NEW PROTON PUMP INHIBITOR, 2-AMINO-4,5-DIHYDROPYRIDO[1,2-A]THIAZOLO [5,4-G] BENZIMIDAZOLE (YJA20379-5)

This study was designed to determine biochemical and pharmacological p roperties of a newly synthesized benzimidazole derivative, 2-amino-4,5 -dihydropyrido [1,2-a] thiazolo [5,4-g] benzimidazole (YJA20379-5) in vitro and in vivo. In the leaky membrane vesicles of pig gastric mucos a, YJA20379-5 inhibited the K+-stimulated H+,K+-ATPase activity in a c oncentration-and time-dependent manner, with IC50 values being 43 mu M and 31 mu M at pH 6.4 and 7.4, respectively. YJA20379-5, given intrad uodenally, had a potent inhibitory effect on the gastric acid secretio n in pylorus-ligated rats. The ED50 value for acid secretion was 15.4 mg/kg. YJA20379-5, administered orally, also suppressed gastric damage s induced by water-immersion stress, indomethacin and ethanol, and duo denal damage induced by mepirizole in rats; the ED50 values were 17.6, 4.7, 3.0 and 18.7 mg/kg, respectively. Furthermore, repeated oral adm inistration of YjA20379-5 accelerated the spontaneous healing of aceti c acid-induced gastric ulcers in rats. It is concluded that the antise cretory activity of YjA20379-5 appears to be associated with inhibitio n of H+,K+-ATPase, while its antigastric and antiduodenal lesion activ ities are primarily related to the antisecretory effect.