Synthesis and biological evaluation of aroylguanidines related to amiloride as inhibitors of the human platelet Na+/H+ exchanger
| Autor: | Didier Laeckmann, Christelle Prosperi-Meys, Jacques Delarge, Bernard Masereel, Joseph Géczy, F. Rogister, Jean Victor Dejardin |
|---|---|
| Rok vydání: | 2002 |
| Předmět: |
Blood Platelets
Sodium-Hydrogen Exchangers Pyrazine Stereochemistry Intracellular pH Clinical Biochemistry Pharmaceutical Science Guanidines Biochemistry Chemical synthesis Amiloride Structure-Activity Relationship chemistry.chemical_compound Drug Discovery medicine Humans Structure–activity relationship Guanidine Molecular Biology chemistry.chemical_classification Ion Transport Molecular Structure Sodium Organic Chemistry Aromatic amine Hydrogen-Ion Concentration Sodium–hydrogen antiporter Logistic Models chemistry Molecular Medicine medicine.drug |
| Zdroj: | Bioorganic & Medicinal Chemistry. 10:1793-1804 |
| ISSN: | 0968-0896 |
| DOI: | 10.1016/s0968-0896(02)00022-6 |
| Popis: | 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). |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect