Synthesis and Na⁺/H⁺ exchanger 1 inhibitory activity of substituted benzoylguanidine-trimetazidine conjugates

In order to search for drugs with protective effects against myocardial ischemic-reperfusion injury,and study the structure-activity relationship of benzoylguanidine derivatives,a novel series of 4-[4-(2,3,4-trimethoxybenzyl)piperazin-1-yl]-methyl and 4-{1-[4-(2,3,4-trimethoxy -benzyl)piperazin-1-yl]}-ethyl benzoylguanidine derivatives were designed and synthesized,and their structures were characterized by MS,IR,^1H NMR.Na⁺/H⁺ exchanger 1 (NHE1) inhibitory activity of twelve target compounds was evaluated in a rat platelet swelling assay.Among all the tested compounds,the IC₅₀ values of compounds 9b and 9c were 4.7 and 4.3 times more potent than cariporide(IC₅₀=12.1 nmol/L),respectively.