500593-84-0Relevant academic research and scientific papers
A novel class of sodium/calcium exchanger inhibitor: Design, synthesis, and structure-activity relationships of 3,4-dihydro-2(1H)-quinazolinone derivatives
Hasegawa, Hirohiko,Muraoka, Masami,Ohmori, Mikiko,Matsui, Kazuki,Kojima, Atsuyuki
, p. 3721 - 3735 (2007/10/03)
Design, synthesis, and structure-activity relationships of 3,4-dihydro-2(1H)-quinazolinone derivatives as inhibitors of the sodium/calcium (Na+/Ca2+) 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+/Ca2+ exchanger, 12g (SM-15811), was discovered. In particular, SM-15811 directly inhibited the Na+-dependent Ca2+ 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 +/Ca2+ inhibitors could have a therapeutic potential for the treatment of ischemic reperfusion injury.
