Introduction

Identification of selective EPAC1 inhibitors that have shown, in animal models, to have therapeutic activity in I / R myocardial damage and to inhibit cardiac remodeling induced by activation of β-ARs.

Technical features

Since the crucial role of EPAC1 inhibition in the therapy of many heart diseases was known, an Epac1-BRET system was used to identify small molecules with inhibitory activity against EPAC1. This led to thieno [2.3-b] pyridine derivatives which showed an interesting antagonist activity against EPAC1. Furthermore, the compounds have been shown to be selective towards other EPAC isoforms. In cellular and animal model assays the compounds reported showed therapeutic activity against cardio-myocytic hypertrophy and in the reduction of myocardial damage from infarction following ischemia re-perfusion. Furthermore, the compounds reduced cardiac remodelling mediated by chronic β-adrenergic receptor activation. State of the art The compounds reported represent an innovation for the treatment of heart failure. Furthermore, the few known EPAC1 antagonists are substrate analogs with little selectivity and poor drug-like properties. The goodness of the therapeutic activity of the compounds reported is also confirmed in the animal model.

Possible Applications

• Pharmaceutical chemistry;
• Treatment of EPAC1-dependent heart diseases such as cardiac arrhythmia and heart failure.

Advantages

• Reduction of side effects by acting on the effector enzymes of cAMP homeostasis such as EPAC;
• Inhibition of cardiac remodelling induced by β-ARs activation;
• Compounds reported have shown a selective inhibition of the EPAC1 enzyme;
• Greater safety than the therapies in use today.