S. Lee et al. / Bioorg. Med. Chem. Lett. 19 (2009) 1329–1331
1331
Additionally cardioprotective in vivo efficacy was determined by
measuring a ratio of myocardial infarction size to area at risk (IS/
AAR) by using a rat myocardial infarction model13 that was stabi-
lized for 20 min after a left thoracotomy operation, subjected to
45 min coronary artery occlusion, following 90 min reperfusion.
The vehicle or compounds were intravenously administered by bo-
lus injection at 5 min prior to onset of ischemia into the femoral
vein.
cardioprotective efficacies were not well correlated each other.
Among a series of imidazole analogues, the 2,5-disubstituted phe-
nyl derivatives, especially 2,5-dichloro 52 and 2-methoxy-5-chloro
54 compounds showed the potent inhibitory activity on NHE-1,
and good in vitro and in vivo cardioprotective efficacy against
ischemia/reperfusion injury. Continuing studies including pharma-
cokinetic and metabolic studies are underway to identify the new
cardioprotective agent.
2,5-Dichloro 52 (59% RPP, 25 mmHg LVEDP) and 2-methoxy-5-
chloro 54 (60% RPP, 28 mmHg LVEDP) significantly improved the
recovery of cardiac contractility and contracture compared with
vehicle (16% RPP, 55 mmHg LVEDP), that is similar to or slightly
better than that of cariporide (48% RPP, 22 mmHg LVEDP). Both
52 and 54 represented potent protective effect in rat myocardial
infarction model, showing 40% and 34% IS/AAR compared with
59% of the vehicle, which seemed to be similar or superior to car-
iporide (41% IS/AAR). In the case of furan analogues, functionality
adjacent to the acylguanidine moiety improved NHE-1 inhibitory
potency, but did not show any significant protective activity
against ischemia-reperfusion injury in the Langendorff model.15
Even none of compounds display protective efficacy in the rat myo-
cardial infarction model. Then, there might be a possibility that the
differences are presumably attributable to the 3-substituents next
to 2-acylguanidine. But this imidazole analogues with methyl
group next to acylguanidine, showed good correlation between
NHE-1 inhibitory potency and both in vitro and in vivo cadiopro-
tective efficacies. The oxazole analogues gave the somehow com-
plicated results. 2,5-Dichloro compound 80 significantly reduced
infarct size (39% IS/AAR) with the potent NHE-1 inhibitory activity,
but didn’t show any protective efficacy in Langendorff experiment.
In the case of 2,5-dimethyl compound 73 markedly improved car-
diac contractile function and contracture (59% RPP, 9 mmHg
LVEDP), however was not protective in rat myocardial infarction
model. It needs more studies to explain those discrepancies.
In summary, a series of (2-aryl-5-methylimidazol-4-ylcarbon-
yl)guanidines and (2-aryl-5-methyloxazol-4-ylcarbonyl)guani-
dines were synthesized and evaluated for their NHE-1 inhibitory
activities and in vitro and in vivo cardioprotective efficacies. Oxa-
zole analogues showed poent NHE-1 inhibitory activities compara-
ble to furan and imidazole compounds, but in vitro and in vivo
Acknowledgment
This research was supported by grants from the Center for Bio-
logical Modulators of the 21st Century Frontier R&D program, the
Ministry of Education, Science and Technology, Korea.
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