Referenced in: none

Automatically associated channels: Kir2.3 , Slo1

Title: Atropisomeric 3-(beta-hydroxyethyl)-4-arylquinolin-2-ones as Maxi-K potassium channel openers.

Authors: Vivekananda M Vrudhula, Bireshwar Dasgupta, Jingfang Qian-Cutrone, Edward S Kozlowski, Christopher G Boissard, Steven I Dworetzky, Dedong Wu, Qi Gao, Roy Kimura, Valentin K Gribkoff, John E Starrett

Journal, date & volume: J. Med. Chem., 2007 Mar 8 , 50, 1050-7

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/17274609

Abstract
The synthesis of a series of 3-beta-hydroxyethyl-4-arylquinolin-2-ones is described. These compounds contain hydrophilic and hydrophobic substituents ortho to the phenolic OH in the C ring of the quinolinone. Electrophysiological evaluation of the panel of compounds revealed that 11 and 16 with an unbranched ortho substituent retain activity as maxi-K ion channel openers. Members of this series of compounds can exist as stable atropisomers. Calculated estimates of the energy barrier for rotation around the aryl-aryl single bond in 3 is 31 kcal/mol. The atropisomers of (+/-)-3, (+/-)-4, and (+/-)-11 were separated by chiral HPLC and tested for their effect on maxi-K mediated outward current in hSlo injected X. laevis oocytes. The (-) isomer in each case was found to be more active than the corresponding (+) isomer, suggesting that the ion channel exhibits stereoselective activation. X-ray crystallographic structures of (+)-3 and (+)-11 were determined. Evaluation of the stability of (-)-3 at 80 degrees C in n-butanol indicated a 19.6% conversion to (+)-3 over 72 h. In human serum at 37 degrees C (-)-3 did not racemize over the course of the 30 h study.