AUGMENTING PARASYMPATHETIC ACTIVITY IN HEART FAILURE PATIENTS: DISCOVERY OF A NOVEL CLASS OF NAPHTHYRIDINE CARBOXAMIDES AS HIGHLY SELECTIVE POSITIVE ALLOSTERIC MODULATORS OF THE M2 RECEPTOR

The talk describes the identification, optimization work and preclinical characterization of a highly selective, first in class positive allosteric modulator (PAM) of the muscarinic M2 acetylcholine receptor. The M2 receptor is mainly expressed within the heart and is the key component of the parasympathetic nervous system. Beta-blockers have been used successfully to target the sympathetic nervous system, however there is no drugs targeting the parasympathetic branch of the autonomic nervous system. Impaired parasympathetic tone has been associated with higher mortality in heart failure, independent of beta-blocker treatment. We describe the ultra-high-throughput screening (uHTS)-based discovery of a novel class of naphthyridine carboxamides as M2 PAMs. The extensive optimization of the screening hit in terms of potency, permeation, metabolic stability and solubility ultimately led to the discovery of the clinical candidate BAY 2413555. The compound shows a very high selectivity towards all other muscarinic receptors and long-lasting pharmacological effects and is suitable for once-daily dosing. This modulator showed no clinically relevant safety findings in a first phase 1 study. With an excellent pharmacokinetic profile, BAY 2413555 could be an ideal treatment option for heart failure patients to increase parasympathetic tone and thus restore autonomic balance.