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 (<b>27</b>). 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.
Authors
- Henrik Teller
- Hanna Tinel (ORCID: https://orcid.org/0000-0002-5518-384X)
- Tobias Marquardt
- Martina Schäfer
- Joachim Mittendorf
- Daniel Basting
- Jörg Hüser (ORCID: https://orcid.org/0000-0001-7261-7171)
- Matthias Wittwer (ORCID: https://orcid.org/0000-0003-1359-4795)
- Thorsten Poethko
- Katrin Nowak‐Reppel
- Maximilian Kullmann
- Dieter Lang (ORCID: https://orcid.org/0000-0002-2968-638X)
- Michael Heckmann (ORCID: https://orcid.org/0009-0003-7731-9941)
- Mark Meininghaus (ORCID: https://orcid.org/0000-0003-0388-2128)
- Alexandros Vakalopoulos (ORCID: https://orcid.org/0000-0002-7032-0304)
- Thomas Mondritzki (ORCID: https://orcid.org/0000-0003-0162-773X)
- Markus Brechmann
- Carsten Terjung (ORCID: https://orcid.org/0000-0002-8202-9231)
- Till Freudenberger (ORCID: https://orcid.org/0000-0003-3144-9591)
- Alexander Straub (ORCID: https://orcid.org/0000-0002-6749-9710)
- Thomas Müller (ORCID: https://orcid.org/0000-0001-9017-4781)
- Melissa Boultadakis Arapinis
Institutions
- Roche (Switzerland) (CH)
- Witten/Herdecke University (DE)
- Axxam (Italy) (IT)
- BioNTech (Germany) (DE)
- Nuvisan (Germany) (DE)
- Bayer (Germany) (DE)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2024-10-28
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c01590
- Citations
- 2
- Primary Topic
- Receptor Mechanisms and Signaling
- Type
- article
- Field-Weighted Citation Impact
- 0.47