2. Academic Validation
  3. New Generation of sGC Stimulators: Discovery of Imidazo[1,2- a]pyridine Carboxamide BAY 1165747 (BAY-747), a Long-Acting Soluble Guanylate Cyclase Stimulator for the Treatment of Resistant Hypertension

New Generation of sGC Stimulators: Discovery of Imidazo[1,2- a]pyridine Carboxamide BAY 1165747 (BAY-747), a Long-Acting Soluble Guanylate Cyclase Stimulator for the Treatment of Resistant Hypertension

  • J Med Chem. 2023 Apr 11. doi: 10.1021/acs.jmedchem.2c02082.
Alexandros Vakalopoulos 1,  Frank Wunder 1,  Ingo V Hartung 1,  Gorden Redlich 1,  Rolf Jautelat 1,  Philipp Buchgraber 1,  Jorma Hassfeld 1,  Alexey V Gromov 1,  Niels Lindner 1,  Donald Bierer 1,  Jörg Gries 1,  Walter Kroh 1,  Holger Paulsen 1,  Joachim Mittendorf 1,  Dieter Lang 1,  Eva Becker-Pelster 1,  Damian Brockschnieder 1,  Volker Geiss 1,  Volkhart Li 1,  Alexander Straub 1,  Andreas Knorr 1,  Thomas Mondritzki 1 2,  Hubert Trübel 1 2,  Marian Raschke 1,  Martina Schaefer 1 3,  Dirk Thomas 1,  Peter Sandner 1 4,  Johannes-Peter Stasch 1 5,  Markus Follmann 1
Affiliations

Affiliations

  • 1 Pharmaceuticals, Research and Development, Bayer AG, Aprather Weg 18a, 42113 Wuppertal, Germany.
  • 2 University of Witten/Herdecke, 58455 Witten, Germany.
  • 3 Lead Discovery, Nuvisan ICB GmbH, Muellerstrasse 178, 13353 Berlin, Germany.
  • 4 Department of Pharmacology, Hannover Medical School, 30625 Hannover, Germany.
  • 5 Institute of Pharmacy, Martin Luther University, 06120 Halle, Germany.
PMID: 37040336 DOI: 10.1021/acs.jmedchem.2c02082
Abstract

Herein, we describe the identification, chemical optimization, and preclinical characterization of novel soluble Guanylate Cyclase (sGC) stimulators. Given the very broad therapeutic opportunities for sGC stimulators, new tailored molecules for distinct indications with specific pharmacokinetics, tissue distribution, and physicochemical properties will be required in the future. Here, we report the ultrahigh-throughput (uHTS)-based discovery of a new class of sGC stimulators from an imidazo[1,2-a]pyridine lead series. Through the extensive and staggered optimization of the initial screening hit, liabilities such as potency, metabolic stability, permeation, and solubility could be substantially improved in parallel. These efforts resulted ultimately in the discovery of the new sGC stimulators 22 and 28. It turned out that BAY 1165747 (BAY-747, 28) could be an ideal treatment alternative for patients with hypertension, especially those not responding to standard anti-hypertensive therapy (resistant hypertension). BAY-747 (28) demonstrated sustained hemodynamic effects up to 24 h in phase 1 studies.

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