title: Synthesis and biological evaluation of aroylguanidines related to amiloride as inhibitors of the human platelet Na(+)/H(+) exchanger.
abstract: Pyridine and benzene bioisosteres of amiloride were synthesized and evaluated for their inhibitory potency against the sodium-hydrogen exchanger (NHE) involved in intracellular pH regulation. The inhibition of NHE was determined by using the platelet swelling assay (PSA) in which the swelling of human platelets was induced by their incubation in an acid buffer (pH 6.7). Additionally, the inhibitory potency of the most active compounds was assessed by measuring the inhibition of the EIPA-sensitive (22)Na(+) uptake (UIA) by human platelets after intracellular acidosis. The results indicated that several benzene derivatives and compounds bearing an carbonylguanidine moiety in the meta position of the pyridine nitrogen were much more potent than amiloride (PSA:IC(50)=43.5 microM; UIA:IC(50)=100.1 microM), but less than EIPA, a pyrazine NHE inhibitor (PSA:IC(50)=0.08 microM; UIA:IC(50)=0.5 microM). In both biological assays (2-amino-5-bromo-pyridine-3-carbonyl)guanidine (32) was the most active molecule (PSA: IC(50)=0.8 microM, UIA : IC(50)=0.8 microM). Our investigations demonstrated that the replacement of the pyrazine ring of amiloride by a pyridine or a phenyl ring improved the NHE inhibitory potency (phenyl >pyridine >pyrazine).
authors.affiliation: Department of Medicinal Chemistry, Natural and Synthetic Drugs Research Center, Université de Liège, CHU, 1 avenue de l'Hôpital, B 36, tour 4, B-4000, Liège, Belgium. d.laeckmann@ulg.ac.be
authors.forename: Didier
authors.initials: D
authors.lastname: Laeckmann
authors.forename: Françoise
authors.initials: F
authors.lastname: Rogister
authors.forename: Jean Victor
authors.initials: JV
authors.lastname: Dejardin
authors.forename: Christelle
authors.initials: C
authors.lastname: Prosperi-Meys
authors.forename: Joseph
authors.initials: J
authors.lastname: Géczy
authors.forename: Jacques
authors.initials: J
authors.lastname: Delarge
authors.forename: Bernard
authors.initials: B
authors.lastname: Masereel
mesh_terms: D000584:Amiloride / Q000737:chemistry*; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism*; D006146:Guanidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D017136:Ion Transport / Q000187:drug effects; D016015:Logistic Models; D015394:Molecular Structure; D012964:Sodium / Q000378:metabolism; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D006146:Guanidines; D017923:Sodium-Hydrogen Exchangers; D000584:Amiloride; D012964:Sodium