title: Synthesis and structure-activity relationships of 6-{4-[(3-fluorobenzyl)oxy]phenoxy}nicotinamide derivatives as a novel class of NCX inhibitors: a QSAR study.
abstract: The sodium-calcium exchanger (NCX) transports Na+ and Ca2+ ions, and controls the Ca2+ concentration in myocytes. Calcium overload is induced via activation of reverse NCX, and is responsible for reperfusion injury in heart failure. Hence, NCX is an attractive target for prevention and treatment of reperfusion arrhythmias, myocardial contracture, and necrosis. We have synthesized a series of 6-{4-[(3-fluorobenzyl)oxy]phenoxy}nicotinamide derivatives, and evaluated their inhibitory activity against the reverse and forward modes of NCX. N-(3-Aminobenzyl)-6-{4-[(3-fluorobenzyl)oxy]phenoxy}nicotinamide (8) was shown to be a potent inhibitor of reverse NCX activity, with an IC50 value of 0.24 microM. A QSAR study showed that inhibition of reverse NCX activity by 6-{4-[(3-fluorobenzyl)oxy]phenoxy}nicotinamide derivatives is multiply dependent on the hydrophobicity (pi) and the shape (B(iv)) of the substituent at the 3-position of the phenyl ring.
authors.affiliation: Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co. Ltd, 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. 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: Ippei
authors.initials: I
authors.lastname: Sato
authors.forename: Issei
authors.initials: I
authors.lastname: Tsukamoto
authors.forename: Taku
authors.initials: T
authors.lastname: Taguchi
authors.forename: Shuichi
authors.initials: S
authors.lastname: Sakamoto
mesh_terms: D009682:Magnetic Resonance Spectroscopy; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors*; D016339:Spectrometry, Mass, Fast Atom Bombardment
chemical_list: C502754:6-(4-((3-fluorobenzyl)oxy)phenoxy)nicotinamide; D019831:Sodium-Calcium Exchanger; D009536:Niacinamide