Synthesis and Structure−Activity Relationships of Cetiedil Analogues as Blockers of the Ca²⁺-Activated K⁺Permeability of Erythrocytes

Abstract

Cetiedil, [2-cyclohexyl-2-(3-thienyl)ethanoic acid 2-(hexahydro-1H-azepin-1-yl)ethyl ester], which blocks the intermediate calcium-activated potassium ion permeability (IK(Ca)) in red blood cells, was used as a lead for investigating structure-activity relationships with the aim of determining the pharmacophore and of synthesizing agents of greater potency. A series of compounds having structures related to cetiedil was made and tested on rabbit erythrocytes. Channel blocking activity within the series was found to correlate well with octanol-water partition coefficients but not with the specific chemical structure of the acid moiety. However, whereas log P for the compounds spans a range of values over 4 orders of magnitude, potency only increases by 2 orders. This suggests that hydrophobic interactions with an active site on the channel are probably not the main determinants of activity. It seems more likely that increased lipophilicity enhances access to the channel, probably from within the cell membrane. In keeping with this interpretation, cetiedil methoiodide was found to be inactive. Triphenylethanoic was found to be a more effective acid grouping than 2-cyclohexyl-2-(3-thienyl)ethanoic, and its 2-(hexahydro-1H-azepin-l-yl)ethyl ester (11) was approximately 3 times more potent than cetiedil. The 9-benzylfluoren-9-yl carboxylic acid ester (21) was found to be approximately 9 times more active than cetiedil, and replacing -CO(2)- in 21 by an ethynyl (-C identical to C-) linkage (compound 26, UCL 1608) increased potency by some 15-fold over that of cetiedil.

Modulators of Small- and Intermediate-Conductance Calcium-Activated Potassium Channels and their Therapeutic Indications

“…(3)). The authors noted that potency tightly correlated with lipophilicity and that the SAR in general was very flat [228]. An increase in logP over 4 orders of magnitude only increased potency by 2 orders.…”

Expression and Role of the Intermediate-Conductance Calcium-Activated Potassium Channel KCa3.1 in Glioblastoma

“…From chemical modification of cetiedil several more potent KCa3.1 channel blockers were obtained. The investigation of one of these compounds, the UCL 1608, suggests that they interact with a lipophilic-binding site located within the membrane [48]. Also the chemical modification of the poorly selective CTL has led to the production of several more effective KCa3.1 channel blockers, including the triarylmethanes TRAM-34 [49] and ICA-17043 [50].…”

Genetic neural network modeling of the selective inhibition of the intermediate-conductance Ca2+-activated K+ channel by some triarylmethanes using topological charge indexes descriptors

“…In some previous QSAR reports, ion channel inhibitory activity had been successfully modeled by means of ANN approach [7,23,24]. Calcium channel antagonist activity of a large set of 1,4 dihydropyridines was modeled using a hybrid principal components (PC)-Neural Network approach, in which, among other methods, they used also a GA routine for selecting the best subset of components for network training [23].…”

“…These include quinine and quinidine, some carbocyanine dyes, charybdotoxin, dequalinium and some of its derivatives, nifedipine, nitrendipine, cetiedil and clotrimazole and some related compounds [7].…”