title: 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.
authors.affiliation: Laboratory of Medicinal Chemistry, University of Liège, 1 avenue de l'Hôpital (B36), B-4000 1, Liège, Belgium.
authors.forename: F
authors.initials: F
authors.lastname: Rogister
authors.forename: D
authors.initials: D
authors.lastname: Laeckmann
authors.forename: P
authors.initials: P
authors.lastname: Plasman
authors.forename: F
authors.initials: F
authors.lastname: Van Eylen
authors.forename: M
authors.initials: M
authors.lastname: Ghyoot
authors.forename: C
authors.initials: C
authors.lastname: Maggetto
authors.forename: J
authors.initials: J
authors.lastname: Liégeois
authors.forename: J
authors.initials: J
authors.lastname: Géczy
authors.forename: A
authors.initials: A
authors.lastname: Herchuelz
authors.forename: J
authors.initials: J
authors.lastname: Delarge
authors.forename: B
authors.initials: B
authors.lastname: Masereel
mesh_terms: D000584:Amiloride / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D001554:Benzene / Q000737:chemistry*; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D002132:Calcium Radioisotopes / Q000493:pharmacokinetics; D004232:Diuretics / Q000138:chemical synthesis / Q000494:pharmacology; D019791:Guanidine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology*; D006146:Guanidines / Q000737:chemistry*; D006801:Humans; D020128:Inhibitory Concentration 50; D007340:Insulinoma / Q000378:metabolism; D051381:Rats; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
chemical_list: D002132:Calcium Radioisotopes; D004232:Diuretics; D006146:Guanidines; C445519:N-(2-amino-5-chloro-4-nitrobenzoyl)-N'-(1-naphtylmethyl)guanidine; D019831:Sodium-Calcium Exchanger; D000584:Amiloride; D001554:Benzene; D019791:Guanidine