First Structure-Activity-Relationship Study of Potent G2A Antagonists

  • J Med Chem. 2026 Jun 25;69(12):14309-14332. doi: 10.1021/acs.jmedchem.6c00079.
Victor Hernandez-Olmos  1  2 ,  Jan Heering  1  2 ,  Felix F Lillich  3 ,  Beatrice Marinescu  3 ,  Sheila Nevermann  1  4 ,  Johanna H M Ehrler  3 ,  Dmytro S Radchenko  5 ,  Yurii S Moroz  5  6  7 ,  Astrid Kaiser  3 ,  Andreas Krämer  3 ,  Stefan Knapp  3 ,  Manfred Schubert-Zsilavecz  3 ,  Mohamad Wessam Alnouri  8 ,  Stefan Offermanns  8  9 ,  Dieter Steinhilber  1  2  3 ,  Marco Sisignano  1  2  4 ,  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, 60596 Frankfurt am Main, Germany.
  • 3. Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany.
  • 4. Institute of Clinical Pharmacology, Pharmazentrum Frankfurt/ZAFES, Goethe-University, D-60590 Frankfurt am Main, Germany.
  • 5. Enamine Ltd. 78 Winston Churchill Street, Kyiv 02094, Ukraine.
  • 6. Chemspace LLC, 85 Winston Churchill Street, Suite 1, Kyiv 02094, Ukraine.
  • 7. National Taras Shevchenko University of Kyiv, 60 Volodymyrska Street, Kyiv 01601, Ukraine.
  • 8. Department of Pharmacology, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany.
  • 9. Center for Molecular Medicine, Goethe University Frankfurt, 60590 Frankfurt, Germany.
PMID: 42275469 DOI: 10.1021/acs.jmedchem.6c00079
Abstract

G2A inhibition has recently been proposed as a novel therapeutic approach to treat oxaliplatin-induced neuropathic pain (OINP) and breast Cancer. However, very few G2A antagonists are known to date. In this study, we report the discovery of a novel series of G2A antagonists developed within our research group, along with the first comprehensive structure-activity relationship (SAR) investigation for this class of compounds. Utilizing a rational design approach, we systematically explored the effects of structural modifications on G2A receptor binding and functional activity. The SAR study identified key molecular features critical for potent G2A inhibition. Two of the newly discovered compounds exhibited submicromolar activity and acceptable selectivity profile among GPCRs.

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