Synthesis and structure–activity relationships of 6-{4-[(3-fluorobenzyl)oxy]phenoxy}nicotinamide derivatives as a novel class of NCX inhibitors: a QSAR study

• Published in: Bioorganic & medicinal chemistry Vol. 13; no. 3; pp. 717 - 724
• Main Authors: Kuramochi, Takahiro, Kakefuda, Akio, Sato, Ippei, Tsukamoto, Issei, Taguchi, Taku, Sakamoto, Shuichi
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.02.2005; Elsevier Science
• Subjects: Anti-arrhythmias; Antiarythmic agents; Biological and medical sciences; Cardiovascular system; Magnetic Resonance Spectroscopy; Medical sciences; NCX; Niacinamide - analogs & derivatives; Niacinamide - chemical synthesis; Niacinamide - chemistry; Niacinamide - pharmacology; Pharmacology. Drug treatments; Quantitative Structure-Activity Relationship; Sodium-Calcium Exchanger - antagonists & inhibitors; Sodium–calcium exchanger; Spectrometry, Mass, Fast Atom Bombardment; Traditional QSAR; Anti-arrhythmias; Traditional QSAR; NCX; Sodium–calcium exchanger; Heart; Sodium Ions; Arrhythmia; Prediction; Cardiovascular disease; Antiarrhythmic agent; Calcium Ions; Myocyte; Pyridine derivatives; Sodium calcium exchanger; Prevention; Treatment; Structure activity relation; Heart disease; Organic fluorine compounds; Carboxamide; Ion exchanger; Inhibition; Chemical synthesis; Lipophilicity; Carrier protein; Aromatic amine
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2004.10.047

A series of 6-{4-[(3-fluorobenzyl)oxy]phenoxy}nicotinamide derivatives were prepared, and their inhibitory activities against the reverse and forward modes of the sodium–calcium exchanger were evaluated. The structure–activity relationships for these compounds are discussed, and the results of a QSAR study are presented. The sodium–calcium exchanger (NCX) transports Na + and Ca 2+ ions, and controls the Ca 2+ 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 IC 50 value of 0.24 μM. 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 ( π) and the shape ( B iv) of the substituent at the 3-position of the phenyl ring.