Cardiovascular safety profile of MA-2029, a novel motilin receptor antagonist

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The aim of this study was to assess the cardiovascular effect of MA-2029, a selective motilin receptor antagonist highly expected for the treatment of irritable bowel syndrome (IBS). MA-2029 inhibited the human ether-a-go-go-related gene (hERG) current at 100μg/ml, but shortened action potential duration (APD) in isolated guinea pig papillary muscles at 10 and 100μg/ml and the corrected QT (QTc) interval after oral administration of 30 and 300mg/kg in conscious telemetered dogs. The discrepancy was probably caused by blockade of the Ca^<2+> channel because MA-2029 inhibited the Ca^<2+> current in isolated guinea pig myocytes. MA-2029 at 100μg/ml also decreased the maximum rising velocity and action potential amplitude in the action potential study, indicating that MA-2029 has Na^+ channel blocking potential. In the cardiovascular study, MA-2029 at 30mg/kg induced slight cardiovascular changes such as hypotension, QTc shortening, and PR prolongation possibly caused by Ca^<2+> channel blockade. The plasma concentration at 4hr after 30mg/kg administration was 2.10μg/ml, 200-fold higher than the effective concentration of MA-2029 as a motilin receptor antagonist. These results suggest that MA-2029 has sufficient cardiovascular safety although it inhibits multiple ion channels at supra-effective concentrations. On the other hand, cisapride, an effective IBS drug, showed clear hERG inhibition and APD prolongation at 100ng/ml. Cisapride exhibited a narrow safety margin because it caused QT prolongation potential even at the therapeutic concentration. In conclusion, MA-2029 is a novel drug highly expected for the treatment of IBS with lower cardiovascular risk than cisapride.
日本トキシコロジー学会の論文
2008-12-01

Cardiovascular safety profile of MA-2029, a novel motilin receptor antagonist

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