2. Academic Validation
  3. Development of a Potent and Selective G2A (GPR132) Agonist

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

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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