Studies on MK-208 (YM-11170) a new, slowly dissociable H2-receptor antagonist

MK-208 [3-(((2-(aminoiminomethyl)amino)-4-thiazolyl)-methyl)thio)-N'-(a minosulfonyl) propanimidamide], also known as YM-11170, is a highly potent histamine H2-receptor antagonist in guinea-pig atria, acting via a unique binding mechanism. Unlike ranitidine, the onset of action of this compound was slow and its inhibitory action was difficult to remove from the tissues by repeated washing. Preincubation of atria with ranitidine, however, protected the H2-receptor from these prolonged inhibitory effects of MK-208. The H2-receptor antagonism produced by MK-208 was not surmountable by increasing concentrations of dimaprit. The compound did not alter the response of this tissue to isoproterenol or affect basal atrial rate under conditions where maximal H2-receptor blockade was achieved. In dogs, MK-208 was effective in inhibiting gastric acid secretion evoked by histamine, gastrin and 2-deoxy-D-glucose. Orally, it was approximately 7 times as potent as ranitidine against histamine-induced secretion, and its duration of action was substantially longer. The compound was also highly effective in inhibiting basal acid secretion in chronic gastric fistula rats.