Discovery of BAY 2413555, First Selective Positive Allosteric Modulator of the M2 Receptor to Restore Cardiac Autonomic Balance

Autonomic
disbalance, i.e., sympathetic overactivation and parasympathetic
withdrawal, is a causal driver of disease progression in heart failure.
While sympatholytic drugs are established treatments, no drug therapy
restoring vagal control of cardiac function is available. We report
here the HTS-based discovery of a novel class of 1,8-naphthyridin-4(1H)-one
carboxamides acting as positive allosteric modulators (PAMs) of the
M2 muscarinic acetylcholine receptor (M2R). M2R is the main postsynaptic
myocyte receptor regulating heart rate, electrical conduction, and
contractile strength. Extensive optimization of the screening hit
in terms of potency, permeation, metabolic stability, and solubility
ultimately resulted in the discovery of the first-in-class clinical
candidate BAY 2413555 (27). With an overall technical
profile compatible with once-daily oral administration in a phase
1 study, no apparent effects on blood pressure, and a mechanism that
largely preserves autonomic regulatory capacity, BAY 2413555 could
be the tool to finally study the restoration of autonomic balance.