Description

RA306 is a potent, selective and orally bioavailable CaMKII inhibitor.  RA306 has potent activity on cardiac CaMKII isoforms delta and gamma (IC50 of 15nM and 25nM respectively).  RA306 was orally administered in two independent studies at 30mg/Kg to mouse models of heart failure carrying the mutation in alpha-actin (responsible for dilated cardiomyopathy in humans) for either 2 weeks (twice daily) or 2 months (once daily).  Echocardiography assessment of mice demonstrated RA306 significantly improved cardiac function compared to vehicle controls.  RA306 treatment was associated with inhibition of cardiac phosphorylation of phospholamban (PLN) at theonine-17 demonstrating reduced cardiac CaMKII activity.  Thus, RA306 is a suitable candidate for clinical development in the treatment of heart disease.

Systematic Name: (R)-2-(2-((4-(4-(2-(hydroxymethyl)morpholino)piperidin-1-yl)-2-methoxyphenyl)amino)-7-isopropoxythieno[3,2-d]pyrimidin-6-yl)propan-2-ol

SMILES:  OC[C@@H]1OCCN(C2CCN(C3=CC=C(NC4=NC=C5C(C(OC(C)C)=C(C(C)(C)O)S5)=N4)C(OC)=C3)CC2)C1

Formula:   C29H41N5O5S

Mol Wt: 571.74

PMID:  31038167

References

Reversion of cardiac dysfunction by a novel orally available calcium/calmodulin-dependent protein kinase II inhibitor, RA306, in a genetic model of dilated cardiomyopathy. Beauverger P. et al. Cardiovascular Research (2020) 116, 329–338.

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