title: Synthesis and structure-activity relationships of cetiedil analogues as blockers of the Ca(2+)-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.
authors.affiliation: Departments of Chemistry and Pharmacology, University College London, Gower Street, London WC1E 6BT, U.K.
authors.forename: C J
authors.initials: CJ
authors.lastname: Roxburgh
authors.forename: C R
authors.initials: CR
authors.lastname: Ganellin
authors.forename: S
authors.initials: S
authors.lastname: Athmani
authors.forename: A
authors.initials: A
authors.lastname: Bisi
authors.forename: W
authors.initials: W
authors.lastname: Quaglia
authors.forename: D C
authors.initials: DC
authors.lastname: Benton
authors.forename: M A
authors.initials: MA
authors.lastname: Shiner
authors.forename: M
authors.initials: M
authors.lastname: Malik-Hall
authors.forename: D G
authors.initials: DG
authors.lastname: Haylett
authors.forename: D H
authors.initials: DH
authors.lastname: Jenkinson
mesh_terms: D000818:Animals; D001381:Azepines / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002463:Cell Membrane Permeability; D004912:Erythrocytes / Q000187:drug effects* / Q000378:metabolism; D005449:Fluorenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D000442:Octanols; D011188:Potassium / Q000378:metabolism*; D026902:Potassium Channel Blockers; D011817:Rabbits; D012995:Solubility; D012997:Solvents; D013329:Structure-Activity Relationship; D014867:Water
chemical_list: C437307:1-((9-benzyl)fluoren-9-yl)-4-(hexahydro-1H-azepin-1-yl)but-2-yne; D001381:Azepines; D005449:Fluorenes; D000442:Octanols; D026902:Potassium Channel Blockers; D012997:Solvents; D014867:Water; C006955:cetiedil; D011188:Potassium; D002118:Calcium