Discovery of a novel potent Na + /Ca 2+ exchanger inhibitor: design, synthesis and structure–activity relationships of 3,4-dihydro-2(1 H )-quinazolinone derivatives

Discovery of N-(3-{4-[(3-Fluorobenzyl)oxy]phenoxy}propyl)-2-pyridin-4-ylacetamide as a Potent and Selective Reverse NCX Inhibitor

“…By modifying the piperidine-1-carboxamide moiety, we found that a compound containing a N-propyl-2-pyridin-4-ylacetamide (12), rather than a N-(pyridin-4-ylmethyl)piperidine-1-carboxamide (3), had enhanced reverse NCX inhibitory activity and increased selectivity. Compound 12 (YM-270951) had an IC 50 value of 0.085 mM against reverse NCX and higher selectivity.…”

“…Therefore, reverse NCX inhibitors are currently considered to be beneficial in treating disease states. 10,11) Recently, quinazoline derivatives 12) and a series of benzyloxyphenyl derivatives [13][14][15][16] have been identified as NCX inhibitors. KB-R7943 (1) is one of the most widely known NCX inhibitors, and is used as a tool in heart and renal failure models, 17,18) and SEA0400 (2) is well known as a potent reverse NCX inhibitor that is efficacious in myocardial ischemia-reperfusion injury [19][20][21][22] (Fig.…”

Design, Synthesis, and Structure-Activity Relationships of 3,4-Dihydropyridopyrimidin-2(1H)-one Derivatives as a Novel Class of Sodium/Calcium Exchanger Inhibitor

“…In this system, Val-Met-Arg-Phe-NH 2 (1) and dimethylamiloride (3), which are known inhibitors of the Na (21) showed strongest activity. Since we have investigated the effects of substituents at the 3-position of the 3,4-dihydro-2(1H)-quinazolinone on the activities, 19,20) we introduced a 1-benzylpiperidin-4-yl at the 3-position of 4-phenyl-3,4-dihydropyrido [4,3-d]pyrimidin-2(1H)-one. As we anticipated, compound 26 increased the activity dramatically, showing the strong activity with an IC 30 value of 0.02 mM.…”

“…We have already reported design, synthesis and structureactivity relationships for 3,4-dihydro-2(1H)-quinazolinone derivatives with the inhibitory activities of the Na ϩ /Ca 2ϩ exchanger. 19,20) In the previous article, we disclosed that these studies based on lead compound 8 with a moderate potent inhibitory activity led to the identification of a structurally novel and highly potent inhibitor against the Na ϩ /Ca 2ϩ exchanger 9 (SM-15811), which directly inhibited the Na ϩ -dependent Ca 2ϩ influx via the Na ϩ /Ca 2ϩ exchanger in cardiomyocytes with high potency and exerted the protective effect against myocardial ischemic reperfusion injury (Fig. 2).…”

Synthesis of 3-Aryl-3,4-Dihydroquinazolin-2(1H)-Ones with the Aid of Low-Valent Titanium Reagent (TiCl4-Sm)

“…7 Recently, these compounds have also been reported as Na + /Ca 2+ exchanger inhibitor. 8 The main synthetic approaches to such compounds consist of the condensation of imidates with anthranilic acid, 9 the reaction of anthranilamides with aldehydes, 10 Pd-catalysed cyclisation reaction of aryl-benzyl ureas 11 and the aza-Wittig reactions of α-azido-substituted aromatic imides. 12 Although some of the methods provide useful strategies for the synthesis of these bicyclic compounds, they suffer major drawbacks, such as involving a multistep synthesis, producing low yields, and requiring expensive catalyst, and are, thus, less desirable commerically.…”