Miscony, Zena; (1998) Potassium channel blockers as potential antisickling agents. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

K+ channels play an important role in controlling membrane potential and hence excitability of cells. They are present in all cells and exist as many types, several often being present on the same cell. An area in need of pharmacological exploration is that of calcium-activated potassium channels, one of the subtypes is the intermediate-conductance, voltage insensitive calcium activated K+ channel (IKCa) found in red blood cells. Cetiedil (2-cyclohexyl-2-(3-thienyl)ethanoic acid 2-(hexahydro-1H-azepin-1-y1) ethy1 ester) has been shown to be an inhibitor, with moderate activity, (IC50 = 24.5 M) of the IKCa channel found in erythrocytes. Cetiedil, a known drug originally found to be a peripheral vasodilator has also been reported to exhibit antisickling properties in erythrocytes. This thesis describes the synthesis and biological activity of a series of analogues based on the lead compound, cetiedil, with the aim of designing a more potent and selective blocker. All the compounds synthesised were submitted for pharmacological testing for their ability to inhibit K+ efflux from rabbit erythrocytes. Previous results obtained on the channel had suggested that drug potency correlates well with drug lipophilicity. A series of novel analogues were synthesised for this thesis using established chemical routes to investigate the critical features present in the cetiedil analogue, 2-[N-(5-ethyl-2- methylpiperidino)]ethyl triphenylethanoate (IC50=l.16 M). Exploration of the pharmacophore of 2-[N-(5-ethyl-2-methylpiperidino)]ethyl triphenylethanoate led to a structure-activity analysis designing more potent blockers which were more lipophilic and stereoisomeric. In general, less of a correlation between drug potency and drug lipophilicity was found in comparison to the previous results obtained. This was because certain structural features now seemed to be influencing activity and not only increases in lipophilicity. The presence of an acetylenic moiety was found to be important for activity. The most potent blockers of the series were 1-[9-(benzyl)fluoren-9-y1)]-4-(N-5-ethy1-2- methylpiperidino)-but-2-yne and the corresponding open chain analogue, 1-[(9-benzyl)- fluoren-9-y1)]-4-(N, N-dibutylamino)-but-2-yne with IC50 values of 0.21 ?M and 0.13 ?M respectively. Clotrimazole (dipheny1-(2-chlorophenyl)-N-imidazolyl methane), a known antifungal drug has also recently been shown to be an inhibitor of IKCa in red blood cells with an IC50 value of 0.94 )?M. Based on clotrimazole, a series of heterocyclic and open chain analogues and a series of non-amino analogues were synthesised. The main structural feature of clotrimazole, the trityl group, was retained and investigations into the role of the imidazole moiety, and importance of the substituents and positions of substitution on the aromatic rings was carried out. Pharmacological results obtained indicated that the imidazole ring was not essential for activity. The most active compound found in the heterocyclic and open chain series besides clotrimazole was 3-{N-[1-(2-chlorophenyl)-1, 1-diphenyl]methyl} aminopyridine, IC50 = 1.95 M. In the non-amino analogue series, the most active compound found was also calculated to be the most lipophilic of the series, tris-(4-chlorophenyl)-methanol, IC50 = 0.56 M. In general, less of a correlation between drug potency and drug lipophilicity was observed for the clotrimazole analogues in comparison to the cetiedil analogues synthesised for this thesis. Stereochemical assignments have been carried out for this thesis using 2D NMR techniques namely one bond heteronuclear shift correlations and nuclear Overhauser enhancements. Lipophilicity throughout the thesis has been expressed as calculated log P values using the manual fragmental method, ( f) of Rekker and the computerised CLOGP method of Leo and Hansch. A drug solubility analysis involving UV spectroscopy was also carried out.

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