Cardioselective anti-ischemic ATP-sensitive potassium channel (KATP) openers: benzopyranyl indoline and indole analogues.
This paper describes the design, syntheses, and biological evaluations of novel ATP-sensitive potassium channel (K(ATP)) openers, benzopyranyl indoline and indole derivatives. Among those, two enantiomers of indoline-2-carboxylic ethyl esters (14, 18) showed the best cardioprotective activities both in vitro and in vivo, while their vasorelaxation potencies were very low (concentration for 50% inhibition of vasorelaxation >30 microM). The cardioprotective effect of 14 was completely reversed by 5-hydroxydecanoate, a selective mitochondrial K(ATP) blocker, indicating its provable protective mechanism through the mitochondrial K(ATP) opening. In addition, we performed conformational analyses using 2D-NMR, X-ray crystallography and molecular modeling to study the structure-activity relationships in this series of compounds.
Lee
Sunkyung
S
Medicinal Science Division, Korea Research Institute of Chemical Technology, 100 Jang-dong, Yoosung-gu, Taejon 305-600, South Korea.
Yi
Kyu Yang
KY
Kim
Soo-Kyung
SK
Suh
Jeehee
J
Kim
Nak Jeong
NJ
Yoo
Sung-eun
SE
Lee
Byung Ho
BH
Seo
Ho Won
HW
Kim
Sun-Ok
SO
Lim
Hong
H
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D001578:Benzopyrans / Q000037:antagonists & inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000037:antagonists & inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D003652:Decanoic Acids / Q000494:pharmacology; D006880:Hydroxy Acids / Q000494:pharmacology; D007211:Indoles / Q000037:antagonists & inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D017202:Myocardial Ischemia / Q000517:prevention & control*; D015221:Potassium Channels / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014664:Vasodilation / Q000187:drug effects
D001578:Benzopyrans; D002316:Cardiotonic Agents; D003652:Decanoic Acids; D006880:Hydroxy Acids; D007211:Indoles; D015221:Potassium Channels; C052853:5-hydroxydecanoic acid; C057812:indoline; D000255:Adenosine Triphosphate