Atropisomeric 3-(beta-hydroxyethyl)-4-arylquinolin-2-ones as Maxi-K potassium channel openers.
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.
Vrudhula
Vivekananda M
VM
Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, Connecticut 06492, USA. vivekananda.vrudhula@bms.com
Dasgupta
Bireshwar
B
Qian-Cutrone
Jingfang
J
Kozlowski
Edward S
ES
Boissard
Christopher G
CG
Dworetzky
Steven I
SI
Wu
Dedong
D
Gao
Qi
Q
Kimura
Roy
R
Gribkoff
Valentin K
VK
Starrett
John E
JE
D000818:Animals; D018360:Crystallography, X-Ray; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D015640:Ion Channel Gating; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000187:drug effects* / Q000502:physiology; D015394:Molecular Structure; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013816:Thermodynamics; D014982:Xenopus laevis
D051036:Large-Conductance Calcium-Activated Potassium Channels; D011804:Quinolines