Atropisomeric 3-(-hydroxyethyl)-4-arylquinolin-2-ones as Maxi-K Potassium Channel Openers
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- 作者：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. Starr
- 刊名：Journal of Medicinal Chemistry
- 出版年：2007
- 出版时间：March 8, 2007
- 年：2007
- 卷：50
- 期：5
- 页码：1050 - 1057
- 全文大小：127K
- 年卷期：v.50,no.5(March 8, 2007)
- ISSN：1520-4804
文摘
The synthesis of a series of 3-
-hydroxyethyl-4-arylquinolin-2-ones is described. These compounds containhydrophilic 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 unbranchedortho substituent retain activity as maxi-K ion channel openers. Members of this series of compounds canexist as stable atropisomers. Calculated estimates of the energy barrier for rotation around the aryl-arylsingle bond in 3 is 31 kcal/mol. The atropisomers of (±)-3, (±)-4, and (±)-11 were separated by chiralHPLC 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, suggestingthat 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% conversionto (+)-3 over 72 h. In human serum at 37 C (-)-3 did not racemize over the course of the 30 h study.
-hydroxyethyl-4-arylquinolin-2-ones is described. These compounds containhydrophilic 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 unbranchedortho substituent retain activity as maxi-K ion channel openers. Members of this series of compounds canexist as stable atropisomers. Calculated estimates of the energy barrier for rotation around the aryl-arylsingle bond in 3 is 31 kcal/mol. The atropisomers of (±)-3, (±)-4, and (±)-11 were separated by chiralHPLC 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, suggestingthat 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% conversionto (+)-3 over 72 h. In human serum at 37 C (-)-3 did not racemize over the course of the 30 h study.