Potent and selective inhibition of the human Na+/H+ exchanger isoform NHE1 by a novel aminoguanidine derivative T-162559.

We isolated Na+/H+ exchanger (NHE)-deficient Chinese hamster ovary (CHO-K1) cells stably expressing human NHE isoforms (hNHE1, hNHE2 and hNHE3) and established an assay system for measuring their Na+/H+ exchange activity by monitoring intracellular pH alterations. Using this assay system, we demonstrated that the acylguanidine derivatives, cariporide and eniporide, cause selective inhibition of hNHE1 (IC50 value of 30 nM for cariporide, IC50 value of 4.5 nM for eniporide). Furthermore, we found that a novel synthetic aminoguanidine derivative, T-162559 ((5E,7S)-[7-(5-fluoro-2-methylphenyl)-4-methyl-7,8-dihydro-5(6H)-quinolinylideneamino] guanidine dimethanesulfonate), causes a selective inhibition of hNHE1 with more potent activity than cariporide and eniporide (IC50 value of 0.96 nM). This compound did not affect Na+/HCO3- cotransport and Na+/Ca2+ exchange.