Compounds that regulate phospholamban phosphorylation with possible cardioprotective effect in the post-infarction heart

Successful acute trombolytic treatment of myocardial infarction (MI, 1.2 mill cases i 7 markets) creates more damaged hearts and a medical need for better post-MI treatment. The adrenalin-beta-adrenergic receptor-cAMP-protein kinase A signalling pathway r egulates heart rate and contractility. Although changes in cardiac myocyte contractility either cause or are associated with cardiovascular disease, surprisingly few drugs are available that modulate the cardiac myocyte cAMP system. Already existing beta- blocking agents reduce cAMP levels only by 50%. New compounds that interfere with the pathway at other levels will serve to make the therapy more potent and/or more targeted avoiding side effects. We have identified a supramolecular complex of the Ca2+ AT Pase Serca2, its regulator phospholamban (PLB), protein kinase A and the A kinase anchoring protein AKAP18d that controls the adrenergic effect on Ca2+ reabsorption and the heart relaxation which is rate limiting for an increased heart rate. Targeting the compartmentalisation of this cAMP signalling complex by specific small molecule PPI inhibitors interferes with adrenalin-induced PKA phosphorylation of PLB, prevents activation of Serca2 and thereby increased energy consumption in the heart. This blockin g effect is believed to be cardio-protective in the post-MI heart. We have screen 80,000 compounds, gone through 2 rounds of screening sub-libraries to identify a set of some 60 hits with effect. We have identified a drug-like lead series that has been de rivatized to improve efficacy 2 orders of magnitude (patent filed). In the proposed optimization project we will test our compounds in whole perfused hearts and living animals with induced post-infarction heart failure to get proof-of-principle in animals along with preclinical data to support a decision to select a lead candidate and backup from the series and do a full preclinical documentation, next leading to a proof-of-concept study with the product in humans.