title: Synthesis and structure-activity relationships of phenoxypyridine derivatives as novel inhibitors of the sodium-calcium exchanger.
abstract: 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.
authors.affiliation: 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>
authors.forename: Takahiro
authors.initials: T
authors.lastname: Kuramochi
authors.forename: Akio
authors.initials: A
authors.lastname: Kakefuda
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Yamada
authors.forename: Ippei
authors.initials: I
authors.lastname: Sato
authors.forename: Taku
authors.initials: T
authors.lastname: Taguchi
authors.forename: Shuichi
authors.initials: S
authors.lastname: Sakamoto
mesh_terms: 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
chemical_list: D011725:Pyridines; D019831:Sodium-Calcium Exchanger; D002118:Calcium