ME-3407, A NEW ANTIULCER AGENT, INHIBITS ACID-SECRETION BY INTERFERING WITH REDISTRIBUTION OF H-K+-ATPASE()

ME-3407 is a newly developed antiulcer drug that markedly promoted the healing of acetic acid-induced chronic ulcers in rats presumably due to potent inhibition of acid secretion. ME-3407 and its metabolites, t he sulfoxide of which was preserved, produced dose-dependent inhibitio n of aminopyrine accumulation by rabbit gastric glands stimulated by a ny agonist, suggesting that the site of their action was downstream ho m the production of second messengers. Although one of the metabolites , EF-4025, showed some inhibitory effects on functional activities of K+-K+-ATPase, ME-3407 itself was not a proton pump inhibitor. ME-3407, but not omeprazole, inhibited the stimulation-associated redistributi on of H+-K+-ATPase from microsomes into the apical membranes in additi on to delocalizing ezrin, a putative F-actin-membrane linker, from api cal plasma membrane. ME-3407 and EF-4025 inhibited myosin light chain kinase (MLCK) and protein kinase A activities. Because another MLCK in hibitor, wortmannin, showed the same properties as ME-3407, i.e., inhi bition of aminopyrine accumulation, inhibition of stimulation-associat ed redistribution of H+-K+-ATPase, and abnormal distribution of ezrin, we hypothesize that MLCK is one of the potential targets for the drug . We conclude that ME-3407 is a promising drug for treating peptic ulc ers, as well as a useful tool for studying mechanisms of parietal cell activation, especially related to the recruitment and recycling of th e proton pump.