Novel inhibitors of the sodium-calcium exchanger: benzene ring analogues of N-guanidino substituted amiloride derivatives

A series of N-guanidino substituted 2,4-diamino-5-carbonylguanidine molecul es related to amiloride were synthesised and, evaluated for their ability t o inhibit the sodium-calcium exchanger in rat insulinoma cells (RINm5F) and human platelets. Specific chemical pathways were used to prepare the benze ne derivatives designed as bioisosteric analogues of the pyrazine derivativ es of amiloride. Several so-called 'simplified analogues', where some subst ituents of amiloride were omitted or replaced, were also prepared and inclu ded in the biological evaluation. The inhibitory potency of the sodium-calc ium exchanger was screened on both cell types by measuring their effect on Ca-45(2+) uptake. Among the most active compounds, N-(2 -amino-5-chloro-4-n itrobenzoyl)-N'-(1-naphtylmethyl)guanidine (IC50 = 3.4 muM) was found more active than amiloride (IC50 = 690 muM) and 3,4-dichlorobenzamil (IC50 = 15. 2 muM), the reference inhibitor. (C) 2001 Editions scientifiques et medical es Elsevier SAS.