Synthesis and Structure-Activity Relationships of Cetiedil Analogues as Blockers of the Ca2+-Activated K+ Permeability of Erythrocytes
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- 作者：Craig J. Roxburgh ; C. Robin Ganellin ; Salah Athmani ; Alessandra Bisi ; Wilma Quaglia ; David C. H. Benton ; Mark A. R. Shiner ; Misbah Malik-Hall ; Dennis G. Haylett ; and Donald H. Jenkinson
- 刊名：Journal of Medicinal Chemistry
- 出版年：2001
- 出版时间：September 27, 2001
- 年：2001
- 卷：44
- 期：20
- 页码：3244 - 3253
- 全文大小：116K
- 年卷期：v.44,no.20(September 27, 2001)
- ISSN：1520-4804
文摘
Cetiedil, [2-cyclohexyl-2-(3-thienyl)ethanoic acid 2-(hexahydro-1H-azepin-1-yl)ethyl ester], whichblocks the intermediate calcium-activated potassium ion permeability (IKCa) in red blood cells,was used as a lead for investigating structure-activity relationships with the aim of determiningthe pharmacophore and of synthesizing agents of greater potency. A series of compounds havingstructures related to cetiedil was made and tested on rabbit erythrocytes. Channel blockingactivity within the series was found to correlate well with octanol-water partition coefficientsbut not with the specific chemical structure of the acid moiety. However, whereas log P for thecompounds spans a range of values over 4 orders of magnitude, potency only increases by 2orders. This suggests that hydrophobic interactions with an active site on the channel areprobably not the main determinants of activity. It seems more likely that increased lipophilicityenhances access to the channel, probably from within the cell membrane. In keeping with thisinterpretation, cetiedil methoiodide was found to be inactive. Triphenylethanoic was found tobe 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. The9-benzylfluoren-9-yl carboxylic acid ester (21) was found to be approximately 9 times moreactive than cetiedil, and replacing -CO2- in 21 by an ethynyl (-C
C-) linkage (compound26, UCL 1608) increased potency by some 15-fold over that of cetiedil.
C-) linkage (compound26, UCL 1608) increased potency by some 15-fold over that of cetiedil.