Targeting Leukocyte Derived MPO in Heart Failure

Heart failure (HF) is a leading cause of mortality, hospitalization and healthcare expenditure in the United States. Despite the aggressive use of current therapies, survival estimates of HF are less than 50% at 5 years after the diagnosis hence it is urgent to develop new therapeutics to inhibit the progression of HF. Among the causes of HF, hypertension caused non-ischemic HF and non-ischemic cardiomyopathy are the most common. Leukocytes are well known to play important roles in the pathogenesis of non-ischemic cardiomyopathy. MPO is a highly abundant enzyme in leucocytes that generates reactive oxidants. Individuals with partial or total MPO deficiency demonstrate a marked reduction in cardiac events yet do not exhibit an increased frequency of infections due to redundant mechanisms of neutrophil killing. Therefore, MPO inhibitors have potential clinical utility to safely combat HF in humans. Due to the potential of targeting leukeocyte-derived MPO in human disease, several groups have developed MPO inhibitors that are undergoing development. We have identified a novel, potent, safe, specific and irreversible class of MPO inhibitors and one of our lead analogues has demonstrated high promise in mouse HF studies. These agents lead to inhibition of MPO activity at the nanomolar level (ex. SA12 IC50 500nM) and inhibit MPO in human neutrophils. SA12 also was found to markedly inhibit pre-established non-ischemic HF in a mouse model as evidenced by echocardiogram measurements demonstrating approximately 10% improvement in ejection fraction (EF) over the course of the study, reduced cardiomegaly, pulmonary edema, cardiac fibrosis and cardiomyocyte hypertrophy. Overall, SA12 and related analogues are promising inhibitors of leukocyte MPO and exhibit potential for the treatment of HF.