2. Academic Validation
  3. From tetrazole to isoquinolinone: Structure-based optimization and late-stage diversification of AR-C118925-derived P2Y2 receptor antagonists

From tetrazole to isoquinolinone: Structure-based optimization and late-stage diversification of AR-C118925-derived P2Y2 receptor antagonists

  • Eur J Med Chem. 2026 Jan 15;302(Pt 2):118335. doi: 10.1016/j.ejmech.2025.118335.
Rayan Aboalgasim Makawi Abdalrahman 1,  Katja Schlegel 2,  Victor Hugo Catricala Fernandes 3,  Adeline Dotz 1,  Giuliano Cesar Clososki 4,  Marcel Bermúdez 5,  Anna Junker 6
Affiliations

Affiliations

  • 1 University of Tuebingen, Department of Preclinical Imaging and Radiopharmacy, Cluster of Excellence iFIT (EXC 2180) "Image-guided and Functionally Instructed Tumor Therapies", Roentgenweg 13, 72076, Tuebingen, Germany.
  • 2 University of Tuebingen, Department of Preclinical Imaging and Radiopharmacy, Cluster of Excellence iFIT (EXC 2180) "Image-guided and Functionally Instructed Tumor Therapies", Roentgenweg 13, 72076, Tuebingen, Germany; Institut für Pharmazeutische und Medizinische Chemie der Universität Münster, Corrensstr. 48, 48149, Münster, Germany.
  • 3 University of Tuebingen, Department of Preclinical Imaging and Radiopharmacy, Cluster of Excellence iFIT (EXC 2180) "Image-guided and Functionally Instructed Tumor Therapies", Roentgenweg 13, 72076, Tuebingen, Germany; Department of Biomolecular Sciences, Faculty of Pharmaceutical Sciences of Ribeirão Preto, University of Sao Paulo, Av. do Café S/N, 14040-903, Ribeirão Preto, SP, Brazil.
  • 4 Department of Biomolecular Sciences, Faculty of Pharmaceutical Sciences of Ribeirão Preto, University of Sao Paulo, Av. do Café S/N, 14040-903, Ribeirão Preto, SP, Brazil.
  • 5 Institut für Pharmazeutische und Medizinische Chemie der Universität Münster, Corrensstr. 48, 48149, Münster, Germany.
  • 6 University of Tuebingen, Department of Preclinical Imaging and Radiopharmacy, Cluster of Excellence iFIT (EXC 2180) "Image-guided and Functionally Instructed Tumor Therapies", Roentgenweg 13, 72076, Tuebingen, Germany. Electronic address: anna.junker@med.uni-tuebingen.de.
PMID: 41223566 DOI: 10.1016/j.ejmech.2025.118335
Abstract

The P2Y2 receptor is a G protein-coupled receptor activated by extracellular nucleotides, is implicated in various pathologies, including Cancer and inflammatory diseases. Despite its therapeutic relevance, potent and selective P2Y2R antagonists remain limited. Here, we report a comprehensive structure-activity relationship (SAR) study based on the clinical tool compound AR-C118925, aiming to enhance P2Y2R selectivity and drug-like properties through bioisosteric replacement of the tetrazole moiety via late-stage diversification. A diverse library of over 60 derivatives was synthesized and evaluated in CA2+-flux assays. Multiple bioisosteres, including isoquinolinone and quinolinone scaffolds, retained or improved P2Y2R antagonistic potency while mitigating off-target activity, especially at P2X receptors. The most potent compound, 32g, demonstrated nanomolar potency (pIC50 = 7.78 ± 0.13) and high selectivity over Other P2X subtypes. Structure-based modeling provided insights into ligand-receptor interactions guiding antagonistic potency. Collectively, these results provide a valuable scaffold for the development of selective and orally bioavailable P2Y2R antagonists.

Keywords

AR-C118925; Antagonists; Bioisosteres; Late-stage diversification; P2Y(2) receptor; Structure-activity relationships.

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