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

Abstract:

:A series of N-guanidino substituted 2,4-diamino-5-carbonylguanidine molecules related to amiloride were synthesised and evaluated for their ability to inhibit the sodium-calcium exchanger in rat insulinoma cells (RINm5F) and human platelets. Specific chemical pathways were used to prepare the benzene derivatives designed as bioisosteric analogues of the pyrazine derivatives of amiloride. Several so-called 'simplified analogues', where some substituents of amiloride were omitted or replaced, were also prepared and included in the biological evaluation. The inhibitory potency of the sodium-calcium exchanger was screened on both cell types by measuring their effect on 45Ca(2+) uptake. Among the most active compounds, N-(2-amino-5-chloro-4-nitrobenzoyl)-N'-(1-naphtylmethyl)guanidine (IC(50)=3.4 microM) was found more active than amiloride (IC(50)=690 microM) and 3,4-dichlorobenzamil (IC(50)=15.2 microM), the reference inhibitor.

journal_name

Eur J Med Chem

authors

Rogister F,Laeckmann D,Plasman P,Van Eylen F,Ghyoot M,Maggetto C,Liégeois J,Géczy J,Herchuelz A,Delarge J,Masereel B

doi

10.1016/s0223-5234(01)01247-8

subject

Has Abstract

pub_date

2001-07-01 00:00:00

pages

597-614

issue

7-8

eissn

0223-5234

issn

1768-3254

pii

S0223523401012478

journal_volume

36

pub_type

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