The biochemical and pharmacological properties of a newly synthesized H+-K+ ATPase inhibitor, 2-dimethylamino-4,5-dihydrothiazolo[4,5 : 3,4]pyridol[1,2-a]benzimidazole

This study was designed to determine the effect of a newly synthesized prot on pump inhibitor, 2-dimethylamino-4,5-dihydrothiazolo[4,5:3,4]pyridol[1,2- a]benzimidazole (YJA20379-2), on gastric H+-K+ ATPase activity, acid secret ion, and experimental gastroduodenal lesions or ulcers in rats. YJA20379-2 inhibited in a concentration-dependent manner the proton pump (H+-K+ ATPase ) activity in isolated hog gastric mucosal microsomes, therefore, confirmin g its classification as a proton pump inhibitor. The inhibitory efficacy of YJA20379-2 on the proton pump was about eight times higher than that of om eprazole at pH 7.4. The activity of the inhibited enzyme was not restored b y dilution and washout method, so this implied that the inhibition of YJA20 379-2 is not reversible. YJA20379-2, given intraduodenally or orally, poten tly suppressed acid secretion in pylorus-ligated rats, with ED50 values of 3.6 and 7.7 mg kg(-1), respectively. Pretreatment with YJA20379-2 dose depe ndently protected the gastric mucosa from damage induced by absolute ethano l, water-immersion stress, indomethacin, and the duodenal mucosa from damag e induced by mepirizole in rats, with ED50 values of 11.0, 21.0, 0.5, and 1 8.7 mg kg(-1), respectively. Repeated administration of YJA20379-2 also dos e dependently accelerated spontaneous healing of acetic acid induced gastri c ulcers. These results suggest that YJA20379-2 has potent antisecretory an d antiulcer effects, which are exerted by suppression of H+-K+ ATPase activ ity in gastric parietal cells, such that YJA20379-2 may be useful for the c linical treatment of peptic ulcer diseases.