Synthesis and Structure-Activity Relationships of 6-Heterocyclic-Substituted Purines as Inactivation Modifiers of Cardiac Sodium Channels
Autor: | Kimberly G. Estep, Douglas S. Krafte, Nancy Dugrenier, Garry M. Pilling, Gerald P. Stankus, Philip M. Carabateas, Kurt A. Josef, Squire Rumney, Paul C. Canniff, William P. Gorczyca, Alan M. Ezrin, Bacon Edward R, G. Maurice Briggs, Kathleen Dillon, Walter A. Volberg |
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Rok vydání: | 1995 |
Předmět: |
Male
Purine Langendorff heart Magnetic Resonance Spectroscopy Xenopus Sodium Guinea Pigs chemistry.chemical_element In Vitro Techniques Pharmacology Contractility Structure-Activity Relationship chemistry.chemical_compound Heterocyclic Compounds In vivo Drug Discovery Animals Humans Purine metabolism Myocardium Sodium channel Effective refractory period Heart Myocardial Contraction chemistry Purines Cats Molecular Medicine Rabbits Sodium Channel Blockers |
Zdroj: | Journal of Medicinal Chemistry. 38:2582-2595 |
ISSN: | 1520-4804 0022-2623 |
Popis: | Purine-based analogs of SDZ 211-500 (5) were prepared and evaluated as inactivation modifiers of guinea pig or human cardiac sodium (Na) channels expressed in Xenopus oocytes. Substances which remove or slow the Na channel inactivation process in cardiac tissue are anticipated to prolong the effective refractory period and increase inotropy and thus have potential utility as antiarrhythmic agents. Heterocyclic substitution at the 6-position of the purine ring resulted in compounds with increased Na activity and potency, with 5-membered heterocycles being optimal. Only minor modifications to the benzhydrylpiperazine side chain were tolerated. Selected compounds which delayed the inactivation of Na channels were found to increase refractoriness and contractility in a rabbit Langendorff heart model, consistent with the cellular mechanism. Activity in both the oocyte and rabbit heart assays was specific to the S enantiomers. Preliminary in vivo activity has been demonstrated following intravenous infusion. The most promising compound on the basis of in vitro data is the formylpyrrole (S)-74, which is 25-fold more potent than DPI 201-106 (1) in the human heart Na channel assay. |
Databáze: | OpenAIRE |
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