Arylsulfonylaminopyridines as Potential Epac Inhibitors: Design, Synthesis and Effects on Myocardial Strips

Exchange proteins directly activated by cyclic AMP (Epac) represent a promising therapeutic target for developing novel cardiotropic agents. Epac-dependent signaling regulates intracellular calcium dynamics, intercellular coupling, and the contractile function of cardiomyocytes. Preclinical studies have demonstrated the potential of Epac2 inhibitors for the treatment of cardiovascular diseases (CVDs).

New potential Epac protein inhibitors from the series of arylsulfonylaminopyridines were designed using pharmacophore modeling, molecular docking, ADMET analysis, and molecular dynamics. The compounds were synthesized via the reaction of N-substituted aminopyridines with arylsulfonyl chlorides. The potential cardiotropic activity of the synthesized compounds was evaluated ex vivo using a model of an isolated rat atrial myocardial strip.

Pharmacophore-based design led to novel aminopyridine derivatives predicted to interact with Epac2. Computational studies suggested stabilization of the inactive conformation of Epac2. Ex vivo experiments revealed changes in myocardial contractility that are consistent with the proposed hypothesis of Epac2 involvement, although further studies are required to establish direct target engagement.

A key objective of this study was to refine the ligand-binding pocket of Epac2, as preliminary in silico analyses revealed discrepancies with previously reported models. In parallel, the potential for PKA-independent Epac2 involvement was assessed using ZMEI-26 in a forskolin-based experimental setup. The combined computational and functional data suggest possible Epac2 engagement and are consistent with the proposed mechanism, although further studies are required to confirm direct target interaction.

A new series of aminopyridine derivatives was created using molecular modeling methods as potential Epac2 inhibitors. During the synthesis, 11 compounds (coded ZMEI) were obtained, several of which (ZMEI-3, ZMEI-15, ZMEI-18, ZMEI-19, ZMEI-22, ZMEI-26, and ZMEI-14) demonstrated the ability to reduce the automaticity and contractility of isolated rat myocardial strips.