Atropisomeric 3-(β-hydroxyethyl)-4-arylquinolin-2-ones as Maxi-K Potassium Channel Openers

• Published in: Journal of medicinal chemistry 2007-03, Vol.50 (5), p.1050-1057
• Main Authors: Vrudhula, Vivekananda M, Dasgupta, Bireshwar, Qian-Cutrone, Jingfang, Kozlowski, Edward S, Boissard, Christopher G, Dworetzky, Steven I, Wu, Dedong, Gao, Qi, Kimura, Roy, Gribkoff, Valentin K, Starrett, John E
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Crystallography, X-Ray; Female; Humans; In Vitro Techniques; Ion Channel Gating; Large-Conductance Calcium-Activated Potassium Channels - drug effects; Large-Conductance Calcium-Activated Potassium Channels - physiology; Medical sciences; Miscellaneous; Molecular Structure; Oocytes - drug effects; Oocytes - physiology; Patch-Clamp Techniques; Pharmacology. Drug treatments; Quinolines - chemical synthesis; Quinolines - chemistry; Quinolines - pharmacology; Stereoisomerism; Thermodynamics; Xenopus laevis
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm061093j

The synthesis of a series of 3-β-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 °C in n-butanol indicated a 19.6% conversion to (+)-3 over 72 h. In human serum at 37 °C (−)-3 did not racemize over the course of the 30 h study.