In the course of our research into new types of non-acylguanidine Na(+)/H(+) exchanger (NHE) inhibitors, we designed and synthesized aryl-fused tetrahydropyranylidene and cyclohexylidene aminoguanidine derivatives I (X = O, CH(2)), which were tested for their inhibitory effects on rat platelet NHEs. After optimization, we found that the S isomer of tetrahydroquinoline derivatives that possess a methyl group in the 4-position and a halogen or methyl group in the o-position of Ar(2) exhibited high inhibitory activity. In these compounds, (5E,7S)-[[7-(5-fluoro-2-methylphenyl)-4-methyl-7,8-dihydro-5(6H)-quinolinylidene]amino]guanidine dimethanesulfonate (18, T-162559) was found to be a potent inhibitor of both rat and human platelet NHEs, with IC(50) values of 14 and 13 nM, respectively. Furthermore, in a rat myocardial infarction model in vivo (1 h ischemia-24 h reperfusion), 18 (0.1 mg/kg, intravenously administered 5 min or 2 h before coronary occlusion) showed significant activity (33% or 23% inhibition, respectively). These results suggested that 18 may exhibit a potent and long-lasting protective activity against cardiac injuries induced by ischemia-reperfusion.