Development of a Potent and Selective G2A (GPR132) Agonist

  • J Med Chem. 2024 Jun 25. doi: 10.1021/acs.jmedchem.3c02164.
Victor Hernandez-Olmos  1  2 ,  Jan Heering  1  2 ,  Beatrice Marinescu  3 ,  Tina Schermeng  4 ,  Vladimir V Ivanov  5 ,  Yurii S Moroz  6  7 ,  Sheila Nevermann  1 ,  Marius Mathes  3 ,  Johanna H M Ehrler  3 ,  Mohamad Wessam Alnouri  8 ,  Markus Wolf  9 ,  Alicia S Haydo  10 ,  Tessa Schmachtel  10 ,  Andrea Zaliani  9 ,  Georg Höfner  11 ,  Astrid Kaiser  3 ,  Manfred Schubert-Zsilavecz  3 ,  Annette G Beck-Sickinger  4 ,  Stefan Offermanns  8  12 ,  Philipp Gribbon  9 ,  Michael A Rieger  9  13  14  15 ,  Daniel Merk  11 ,  Marco Sisignano  16 ,  Dieter Steinhilber  1  2  3 ,  Ewgenij Proschak  1  2  3
Affiliations
  • 1. Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Theodor-Stern-Kai 7, 60596 Frankfurt am Main, Germany.
  • 2. Fraunhofer Cluster of Excellence Immune-Mediated Diseases CIMD, Theodor-Stern-Kai 7, 60596 Frankfurt am Main, Germany.
  • 3. Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Street 9, 60438 Frankfurt am Main, Germany.
  • 4. Institute of Biochemistry, Faculty of Life Sciences, Leipzig University, Brüderstraße 34, 04103 Leipzig, Germany.
  • 5. Enamine Ltd, 67 Chervonotkatska Street, Kyiv 02094, Ukraine.
  • 6. Taras Shevchenko National University of Kyiv, 64 Volodymyrska Street, Kyiv 01601, Ukraine.
  • 7. Chemspace LLC, 85 Chervonotkatska Street, Kyiv 02094, Ukraine.
  • 8. Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Ludwigstr. 43, 61231Bad Nauheim, Germany.
  • 9. Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Discovery Research ScreeningPort, Schnackenburgallee 114, 22525 Hamburg, Germany.
  • 10. Department of Medicine, Hematology/Oncology, Goethe University Hospital Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
  • 11. Department of Pharmacy, Ludwig-Maximilians-Universität München, Butenandtstr. 5-13, 81377 Munich, Germany.
  • 12. Center for Molecular Medicine, Goethe University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany.
  • 13. Frankfurt Cancer Institute, 60590 Frankfurt am Main, Germany.
  • 14. Cardio-Pulmonary Institute (CPI), 60590 Frankfurt am Main, Germany.
  • 15. German Cancer Consortium (DKTK) and German Cancer Research Institute (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
  • 16. Pharmazentrum Frankfurt/ZAFES, Institute of Clinical Pharmacology, Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
PMID: 38917049 DOI: 10.1021/acs.jmedchem.3c02164
Abstract

G protein-coupled receptor G2A was postulated to be a promising target for the development of new therapeutics in neuropathic Pain, Acute Myeloid Leukemia, and inflammation. However, there is still a lack of potent, selective, and drug-like G2A agonists to be used as a chemical tool or as the starting matter for the development of drugs. In this work, we present the discovery and structure-activity relationship elucidation of a new potent and selective G2A agonist scaffold. Systematic optimization resulted in (3-(pyridin-3-ylmethoxy)benzoyl)-d-phenylalanine (T-10418) exhibiting higher potency than the reference and natural ligand 9-HODE and high selectivity among G protein-coupled receptors. With its favorable activity, a clean selectivity profile, excellent solubility, and high metabolic stability, T-10418 qualifies as a pharmacological tool to investigate the effects of G2A activation.

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