ABSTRACT
A series of potent inhibitors of the sodium hydrogen exchanger-1 (NHE-1) is described. Structure-activity relationships identified the 3-methyl-4-fluoro analog 9t as a highly potent (IC50 = 0.0065 microM) and selective (NHE-2/NHE-1=1400) non-acylguanidine NHE-1 inhibitor. Pharmacokinetic studies showed that compound 9t has an oral bioavailability of 52% and a plasma half life of 1.5 h in rats. Because of its promising potency, selectivity, and a good pharmacokinetic profile, compound 9t was selected for further studies.
Subject(s)
Piperidines/chemistry , Piperidines/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacology , Sodium-Hydrogen Exchangers/antagonists & inhibitors , Administration, Oral , Animals , Biological Availability , Inhibitory Concentration 50 , Molecular Structure , Piperidines/chemical synthesis , Piperidines/pharmacokinetics , Pyrimidines/chemical synthesis , Pyrimidines/pharmacokinetics , Rats , Sodium-Hydrogen Exchangers/metabolism , Structure-Activity RelationshipABSTRACT
Inhibition of the sodium hydrogen exchanger isoform-1 (NHE-1) has been shown to limit damage to the myocardium under ischemic conditions in animals. While most known NHE-1 inhibitors are acylguanidines, this report describes the design and synthesis of a series of heterocyclic inhibitors of NHE-1 including aminoimidazoles with undiminished in vitro activity and oral bioavailability.
