4-Substituted (benzo[b]thiophene-2-carbonyl)guanidines as novel Na+/H+ exchanger isoform-1 (NHE-1) inhibitors

KR-33028, a potent inhibitor of the Na+/H+ exchanger NHE1, suppresses metastatic potential of triple-negative breast cancer cells

“…In breast cancer, it is metastasis that is the primary cause of fatality [23]. It stands to reason that 15 modulating the pH of the tumor microenvironment with pharmacological inhibition of NHE1 activity could either prevent or hinder metastasis and is therefore an important area of investigation.…”

“…The use of amiloride in cancer therapy in animal models and clinical trials was recently reviewed [12], as was cariporide and other novel NHE1 inhibitors [13]. In this study, we focused on a new, potent and selective small molecule NHE1 inhibitor, KR-33028 (4-cyano (benzo[b]thiophene-2-carbonyl)guanidine) [14,15]. KR-33028 was previously evaluated for cardioprotective effects [16] and was shown to reduce myocardial infarction due to ischemiareperfusion injury in rats and dogs [17].…”

Pharmacological profile of KR-33028, a highly selective inhibitor of Na+/H+ exchanger

“…Unfortunately, however, KR-32570 has also been found to be non-selective, binding several receptors and inducing acute toxicity in a study involving rats (LD 50 values in rats: 40-50 mg/kg; unpublished data). During the course of our efforts to replace KR-32570, we found that 4-cyano (benzo [b]thiophene-2-carbonyl)guanidine (KR-33028) has no toxicity in animals but does have cardioprotective effects in rat hearts subjected to ischemia and reperfusion (Lee et al, 2005c). Therefore, the present study was performed to evaluate cardioprotective effects of KR-33028 on cell death induced by hypoxia in rat heart-derived H9c2 cells and on ischemia/ reperfusion-induced mechanical and metabolic dysfunction in isolated rat hearts.…”

Dose‐dependent pharmacokinetics of a new Na+/H+ exchanger inhibitor KR‐33028 in rats

“…KR-33028, 4-cyano(benzo [b]thiophene-2-carbonyl) guanidine mesylate ( Figure 1) is an NHE-1 inhibitor with IC 50 of 2.0 mm [10] and exhibits potent cardioprotective effects by inhibition of intracellular Ca 2þ overload and mitochondrial cell death pathway [11]. KR-33028 has no significant acute and subacute toxicity in rats [11].…”