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Kvl.5 channel

Kvl.5 In human atria, the Kvl.5 presents the ultrarapid delayed rectifier that contributes to the repolarization in the early phase of cardiac action potential. Selective blockers of Kvl.5 channels could be potentially beneficial in the treatment of atrial fibrillation because blocking Kvl. 5 could delay repolarization and prolong refractoriness selectively in cardiac myocytes. Examples for Kvl.5 blockers include AVE0118, S9947, and analogs of diphenyl phosphine oxide (DPO). [Pg.995]

Peukert S, Brendel J, Pirard B, Strtibing C, Kleemann HW, Bohme T, Hemmerle H. Pharmacophore-based search, synthesis, and biological evaluation of anthra-nilic amides as novel blockers of the Kvl.5 channel. Bioorg Med Chem Lett 2004 14 2823-7. [Pg.423]

Keywords Antiarrhythmic Atrial fibrillation I-g UI potassium current Kvl.5 channel... [Pg.145]

This review focuses on the recent discovery and development of chemical entities targeting the Kvl.5 potassium channel subunit for the treatment of atrial arrhythmias. This strategy is based on the expression of the ultrarapidly activating delayed rectifier potassium current, /Run in atria but not ventricles of humans, and on the molecular characterization of the Kvl.5 channel subunit as a structural correlate of JRur [1-6]. Although no perfectly selective Kvl.5... [Pg.145]

Some of the other scaffolds used to synthetize Kvl.5 channel inhibitors are prototypes of vicinally substituted heterocycles, such as the tetrazole 2f shown in Table 1. This series was developed to circumvent a metabolic liability of thiazolidinone derivatives previously identified as potent Kvl.5 blockers [54]. Some chemistry efforts have been directed toward novel structures that provide practical advantages in addition to Kvl.5 potency. This is the case of Kvl.5 inhibitors based on a diisopropyl amide scaffold [50]. [Pg.151]

Despite the large variety of molecules recently described as desirable Kvl.5 inhibitors, there has been limited success in predicting ligand-based Kvl.5 pharmacophores. Recently, a pharmacophore model was derived from several members of the bisaryl series (see Table 1) and another series. The model consists of three hydrophobic centers in a triangular arrangement, and it was used to identify anthranilic amides as novel Kvl.5 inhibitors [43]. A similar paucity of published data exists with regard to pharmacophores based on the Kvl.5 channel structure [59]. [Pg.151]

Fig-i Structural considerations about drug binding in the Kvl.5 channel pore. Amino acid sequence comparison of alpha subunit sequences from human Kvl.1-1.6 and Kv2.1, Kvll.l (hERG), Kv7.1 (KvLQTl). Symbols indicate complete amino acid conservation ( ), conservative substitution among all aligned sequences ( ), and critical substitution in a generally conserved position (.)... [Pg.154]

The elucidation of structural pharmacophores in the Kvl.5 channel pore has not been nearly as extensive as analogous efforts conducted on hERG [69]. Briefly, in these types of studies, a drug of interest is used to probe a battery of single amino acid substituted channels with properties similar to wild type channels, to scan a structural domain and identify de-... [Pg.155]

Table 1 Selected Step 6 experimental derivatives and accompanying mass spectra data and Kvl.5 channel inhibition concentration, IC50. H NMR for all entries supplied by the author. Entries 1, 13, 19, and 27 are especially preferred as potassium channel blockers of the Kvl.5 channel... Table 1 Selected Step 6 experimental derivatives and accompanying mass spectra data and Kvl.5 channel inhibition concentration, IC50. H NMR for all entries supplied by the author. Entries 1, 13, 19, and 27 are especially preferred as potassium channel blockers of the Kvl.5 channel...
B. Ultrarapidly Activating Potassium Channel Blockers of the Kvl.5 Channel... [Pg.256]

Ultrarapidly activating potassium Kvl.5 channel blockers consisting of benzamide derivatives, (II), prepared by Baker (4) were effective in treating atrial fibrillation disorders. [Pg.260]

Substituted benzopyran derivatives, (IV), prepared by Ohara (4) were effective as potassium Kvl.5 channel blockers and used in the treatment of arrhythmic events. [Pg.261]

We proposed several mutations to the Kvl.5 channel to validate our model. Docking of our inhibitors in the Kvl.5 binding site revealed Thr477 as very important for binding. Indeed, mutation of Thr477 to serine left the Kvl.5 channel fully functional, but the activity of all four types of Kvl.5 inhibitors significantly decreased [50],... [Pg.233]

Fig. 10 Definition of the pharmacophore query for the Kvl.5 channel. Representatives of the two compound series (A and B) were aligned(b) to derive the pharmacophore (a). (Copyright is permitted by Elsevier). Fig. 10 Definition of the pharmacophore query for the Kvl.5 channel. Representatives of the two compound series (A and B) were aligned(b) to derive the pharmacophore (a). (Copyright is permitted by Elsevier).
Researchers at Aventis described a pharmacophore for Kvl.5 channel blockers consisting of three hydrophobic centers in a triangular arrangement. First observed in an earlier active series [73], the pharmacophore was validated using a database of 423 Kvl.5 blockers [74], The query was able to retrieve 58% of the known actives. A pharmacophore search of the corporate collection identified 27 clusters containing 1975 compounds. Screening the representatives of 18 clusters led to the discovery of an anthranilamide hit molecule (Kvl.5 IC50 = 5.6pM in Xenopus oocytes) [74],... [Pg.365]

This brief literature review provides compelling evidence in favour of a significant role for the sense of taste in fat preference in rodents. However, the presence of several putative lipid receptors (CD36, Kvl.5 channels, GPR120) in taste buds was not expected and raises questions about the physiological roles of these receptors. Furthermore, the taste-mediated perception of LCFA by CD36 would be unusual owing to the multifunctional nature of this protein. [Pg.241]

Caballero R, Valenzuela C, Longobardo M. Effects of rupatadine, a new dual antagonist of histamine and platelet-activating factor receptors, on human cardiac Kvl.5 channels. Br J Pharmacol 1999 128 1071-81. [Pg.352]


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See also in sourсe #XX -- [ Pg.148 ]




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