Discovery of an N-(2-aminopyridin-4-ylmethyl)nicotinamide derivative: a potent and orally bioavailable NCX inhibitor

• Published in: Bioorganic & medicinal chemistry 2005-06, Vol.13 (12), p.4022-4036
• Main Authors: Kuramochi, Takahiro, Kakefuda, Akio, Yamada, Hiroyoshi, Tsukamoto, Issei, Taguchi, Taku, Sakamoto, Shuichi
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Anti-arrhythmics; Antiarythmic agents; Biological and medical sciences; Biological Availability; Calcium - metabolism; Calcium Channel Blockers - chemical synthesis; Calcium Channel Blockers - pharmacology; Cardiovascular system; Cytochrome P-450 Enzyme System - drug effects; Disease Models, Animal; Heart Failure - drug therapy; Humans; Inhibitory Concentration 50; Male; Medical sciences; Myocardial Reperfusion Injury - drug therapy; NCX; Niacinamide - analogs & derivatives; Niacinamide - chemical synthesis; Niacinamide - pharmacology; Pharmacokinetics; Pharmacology. Drug treatments; Rats; Rats, Inbred Strains; Sodium-Calcium Exchanger - antagonists & inhibitors; Sodium–calcium exchanger; Structure-Activity Relationship
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2005.03.052

A series of 2-aminopyridine derivatives were prepared and evaluated for their inhibitory activities against the reverse and forward modes of the sodium–calcium exchanger (NCX). The structure–activity relationships of these compounds and their inhibitory activities against NCX are discussed. N-[(2-Aminopyridin-4-yl)methyl]-6-{4-[(3-fluorobenzyl)oxy]phenoxy}nicotinamide was evaluated for its effect in a heart failure model. Ca 2+ overload in myocardial cells is responsible for arrhythmia. Sodium–calcium exchanger (NCX) inhibitors are more effective than sodium–hydrogen exchanger (NHE) inhibitors with regard to modulation of Ca 2+ overload, because NCX inhibitors can directly inhibit the influx of Ca 2+ into cells. NCX is an attractive target for the treatment of heart failure and ischemia-reperfusion. We have designed and synthesized a series of N-(2-aminopyridin-4-ylmethyl)nicotinamide derivatives, based on compound 5. We have discovered a novel NCX inhibitor ( 23h) with an IC 50 value of 0.12 μM against reverse NCX. The inhibitory activities of our NCX inhibitors against cytochrome P450 were also evaluated. The effects on heart failure and the pharmacokinetic profile of compound 23h are discussed.