2. Academic Validation
  3. Discovery and Structure Relationships of Salicylanilide Derivatives as Potent, Non-acidic P2X1 Receptor Antagonists

Discovery and Structure Relationships of Salicylanilide Derivatives as Potent, Non-acidic P2X1 Receptor Antagonists

  • J Med Chem. 2020 Jun 11;63(11):6164-6178. doi: 10.1021/acs.jmedchem.0c00435.
Maoqun Tian 1,  Aliaa Abdelrahman 1,  Younis Baqi 2,  Eduardo Fuentes 3,  Djamil Azazna 1,  Claudia Spanier 1,  Sabrina Densborn 1,  Sonja Hinz 1,  Ralf Schmid 4 5,  Christa E Müller 1
Affiliations

Affiliations

  • 1 PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany.
  • 2 Department of Chemistry, Faculty of Science, Sultan Qaboos University, P.O. Box 36, 123 Muscat, Oman.
  • 3 Thrombosis Research Center, Medical Technology School, Department of Clinical Biochemistry and Immunohaematology, Faculty of Health Sciences, Interdisciplinary Center on Aging, Universidad de Talca, 3460000 Talca, Chile.
  • 4 Department of Molecular and Cell Biology, University of Leicester, Leicester LE1 7RH, U.K.
  • 5 Leicester Institute of Structural and Chemical Biology, University of Leicester, Leicester LE1 7RH, U.K.
PMID: 32345019 DOI: 10.1021/acs.jmedchem.0c00435
Abstract

Antagonists for the ATP-gated ion channel receptor P2X1 have potential as antithrombotics and for treating hyperactive bladder and inflammation. In this study, salicylanilide derivatives were synthesized based on a screening hit. P2X1 antagonistic potency was assessed in 1321N1 astrocytoma cells stably transfected with the human P2X1 Receptor by measuring inhibition of the ATP-induced calcium influx. Structure-activity relationships were analyzed, and selectivity versus other P2X Receptor subtypes was assessed. The most potent compounds, N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide (1, IC50 0.0192 μM) and N-[3,5-bis(trifluoromethyl)phenyl]-4-chloro-2-hydroxybenzamide (14, IC50 0.0231 μM), displayed >500-fold selectivity versus P2X2 and P2X3, and 10-fold selectivity versus P2X4 and P2X7 receptors, and inhibited collagen-induced platelet aggregation. They behaved as negative allosteric modulators, and molecular modeling studies suggested an extracellular binding site. Besides selective P2X1 antagonists, compounds with ancillary P2X4 and/or P2X7 Receptor inhibition were discovered. These compounds represent the first potent, non-acidic, allosteric P2X1 Receptor antagonists reported to date.

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