ABSTRACT
Multiple delayed rectifier potassium currents, including I(Ks), are responsible for the repolarization and termination of the cardiac action potential, and blockers of these currents may be useful as antiarrhythmic agents. Modification of compound 5 produced 19(S) that is the most potent I(Ks) blocker reported to date with >5000-fold selectivity over other cardiac ion channels. Further modification produced 24A with 23% oral bioavailability.
Subject(s)
Benzamides/chemical synthesis , Oxadiazoles/chemical synthesis , Potassium Channel Blockers , Potassium Channel Blockers/chemical synthesis , Potassium Channels, Voltage-Gated , Administration, Oral , Animals , Benzamides/chemistry , Benzamides/pharmacology , Biological Availability , Chromatography, High Pressure Liquid , Crystallography, X-Ray , Drug Design , In Vitro Techniques , KCNQ Potassium Channels , KCNQ1 Potassium Channel , Oocytes/metabolism , Oocytes/physiology , Oxadiazoles/chemistry , Oxadiazoles/pharmacology , Patch-Clamp Techniques , Potassium Channel Blockers/chemistry , Potassium Channel Blockers/pharmacology , Potassium Channels/metabolism , Rats , Stereoisomerism , Structure-Activity Relationship , XenopusABSTRACT
A novel series of arylcyclopropanecarboxyl guanidines was synthesized and evaluated for activity against the sodium hydrogen exchanger isoform-1 (NHE-1). In biological assays conducted in an AP1 cell line expressing the human NHE-1 isoform, the starting cyclopropane 3a (IC(50) = 3.5 microM) shows inhibitory activity comparable to cariporide (IC(50) = 3.4 microM). Structure-activity relationships are used to optimize the affinity of various acyl guanidines for NHE-1 by screening the effect of substituents at both aryl and cyclopropyl rings. It is demonstrated that introduction of appropriate hydrophobic groups at the phenyl ring and a gem-dimethyl group at the cyclopropane ring enhances the NHE-1 inhibitory activity by up to 3 orders of magnitude (compound 7f, IC(50) = 0.003 microM). In addition, the gem-dimethyl series of analogues seem to display improved oral bioavailability and longer plasma half-life in rats. Furthermore, the lead benzodihydrofuranyl analogue 1 (BMS-284640) shows over 380-fold increased NHE-1 inhibitory activity as well as improved selectivity for NHE-1 over NHE-2 compared to cariporide.
Subject(s)
Cation Transport Proteins , Cyclopropanes/chemical synthesis , Guanidines/chemical synthesis , Membrane Proteins/antagonists & inhibitors , Sodium-Hydrogen Exchangers/antagonists & inhibitors , Administration, Oral , Animals , Biological Availability , Cell Line , Cricetinae , Crystallography, X-Ray , Cyclopropanes/chemistry , Cyclopropanes/pharmacology , Guanidines/chemistry , Guanidines/pharmacology , Humans , Protein Isoforms/antagonists & inhibitors , Rats , Sodium-Hydrogen Exchanger 1 , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Synthesis of a series of alpha-hydroxythiol esters made available, for the first time, product-like molecules that were evaluated as inhibitors of the enzyme glyoxalase I and as potential antitumor agents. All the alpha-hydroxythiol esters tested were competitive inhibitors of the enzyme, albeit weak; however, the relative [I]50 values suggested information about the active site. Antileukemic activity in L1210 lymphoid leukemia indicated no significant activity by these alpha-hydroxythiol esters.
