A novel class of sodium/calcium exchanger inhibitor: design, synthesis, and structure-activity relationships of 3,4-dihydro-2(1H)-quinazolinone derivatives.
Design, synthesis, and structure-activity relationships of 3,4-dihydro-2(1H)-quinazolinone derivatives as inhibitors of the sodium/calcium (Na(+)/Ca(2+)) exchanger are discussed. These studies, based on a lead compound 9a, which was identified in our library, involved systematic modification of three regions and revealed that (1) the 3,4-dihydro-2(1H)-quinazolinone having a tertiary amino alkyl side chain at the 3-position is essential for activity, (2) a nonsubstituted phenyl ring is most suitable for high activity, and (3) introduction of a 4-substituted piperidine moiety enhanced the activity, in particular 4-benzylpiperidin-1-yl showed strong inhibitory activity. Based on these SAR studies, a structurally novel and highly potent inhibitor against the Na(+)/Ca(2+) exchanger, 12g (SM-15811), was discovered. In particular, SM-15811 directly inhibited the Na(+)-dependent Ca(2+) influx via the Na(+)/Ca(2+) exchanger in cardiomyocytes with a high potency. The activity was almost two orders more potent than the lead compound 9a and SM-15811 exerted a protective effect against myocardial ischemic reperfusion injury. These Na(+)/Ca(2+) inhibitors could have a therapeutic potential for the treatment of ischemic reperfusion injury.
Hasegawa
Hirohiko
H
Research Division, Sumitomo Pharmaceuticals Co., Ltd, 1-98, Kasugadenaka 3-Chome, Konohana-ku, Osaka 554-0022, Japan. hhasegaw@sumitomopharm.co.jp
Muraoka
Masami
M
Ohmori
Mikiko
M
Matsui
Kazuki
K
Kojima
Atsuyuki
A
D015195:Drug Design; D009682:Magnetic Resonance Spectroscopy; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors*; D016339:Spectrometry, Mass, Fast Atom Bombardment; D013329:Structure-Activity Relationship
D011799:Quinazolines; D019831:Sodium-Calcium Exchanger