Synthesis and structure-activity relationships of phenoxypyridine derivatives as novel inhibitors of the sodium-calcium exchanger.
The sodium-calcium exchanger (NCX) is known as the transporter that controls the concentration of Ca(2+) in cardiac myocytes. In the setting of heart failure and myocardial ischemia-reperfusion, NCX underlies an arrhythmogenic transient inward current responsible for delayed after--depolarizations and nonreentrant initiation of ventricular tachycardia. NCX is an attractive target for treatment in heart failure and myocardial ischemia-reperfusion. We have designed and synthesized a series of phenoxypyridine derivatives, based on compound 3. These derivatives have been evaluated for their inhibitory activity against both the reverse and forward mode of NCX in CCL39 cells. We have discovered several novel potent NCX inhibitors (39q, 48k), which have a high selectivity for reverse NCX inhibitory activity.
Kuramochi
Takahiro
T
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co. Ltd, 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. kuramochi.takahiro@yamanouchi.co.jp <kuramochi.takahiro@yamanouchi.co.jp>
Kakefuda
Akio
A
Yamada
Hiroyoshi
H
Sato
Ippei
I
Taguchi
Taku
T
Sakamoto
Shuichi
S
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D006224:Cricetinae; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D020128:Inhibitory Concentration 50; D009336:Necrosis / Q000139:chemically induced; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology*; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D011725:Pyridines; D019831:Sodium-Calcium Exchanger; D002118:Calcium