Synthesis and structure-activity relationships of benzyloxyphenyl derivatives as a novel class of NCX inhibitors: effects on heart failure.
In the context of heart failure and myocardial ischemia reperfusion, the activity of the sodium-calcium exchanger can lead to calcium overload, which in turn can lead to contractile dysfunction and arrhythmia. Therefore, NCX is an attractive target for treatment of heart failure and myocardial ischemia reperfusion. We have designed and synthesized a series of benzyloxyphenyl derivatives as potential NCX inhibitors, based on compound 4. These derivatives have been evaluated for their inhibitory activity against both the reverse and forward modes of NCX, and two novel potent NCX inhibitors (7i, 10a) were discovered. Compound 7i was evaluated for its efficacy on ouabain-induced tonotropy and arrhythmia in a heart-failure model.
Kuramochi
Takahiro
T
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co. Ltd, 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. kuramochi.takahiro@yamanouchi.co.jp
Kakefuda
Akio
A
Yamada
Hiroyoshi
H
Ogiyama
Takashi
T
Taguchi
Taku
T
Sakamoto
Shuichi
S
D001593:Benzyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D002303:Cardiac Output, Low / Q000188:drug therapy*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D017202:Myocardial Ischemia / Q000188:drug therapy*; D019831:Sodium-Calcium Exchanger / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D016339:Spectrometry, Mass, Fast Atom Bombardment; D013329:Structure-Activity Relationship
D001593:Benzyl Compounds; D019831:Sodium-Calcium Exchanger