Synthesis and structure-activity relationships of cetiedil analogues as blockers of the Ca2+-activated K+ permeability of erythrocytes

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 (IKCa) in red blood cells, was used as a lead for investi gating structure-activity relationships with the aim of determining the pha rmacophore and of synthesizing agents of greater potency. A series of compo unds having structures related to cetiedil was made and tested on rabbit er ythrocytes. Channel blocking activity within the series was found to correl ate well with octanol-water partition coefficients but not with the specifi c chemical structure of the acid moiety. However, whereas log P for the com pounds spans a range of values over 4 orders of magnitude, potency only inc reases by 2 orders. This suggests that hydrophobic interactions with an act ive site on the channel are probably not the main determinants of activity. It seems more likely that increased lipophilicity enhances access to the c hannel, probably from within the cell membrane. In keeping with this interp retation, cetiedil methoiodide was found to be inactive, Triphenylethanoic was found to be a more effective acid grouping than 2-cyclohexyl-2-(3-thien yl)ethanoic, and its 2-(hexahydro-1H-azepin-l-yl)ethyl ester (11) was appro ximately 3 times more potent than cetiedil. The 9-benzylfluoren-9-yl carbox ylic acid ester (21) was found to be approximately 9 times more active than cetiedil, and replacing -CO2- in 21 by an ethynyl (-C dropC-) linkage (com pound 26, UCL 1608) increased potency by some 15-fold over that of cetiedil .