2. Academic Validation
  3. Exploiting the 2-(1,3,4,9-tetrahydropyrano[3,4- b]indol-1-yl)acetic Acid Scaffold to Generate COXTRANs: A New Class of Dual Cyclooxygenase Inhibitors-Thromboxane Receptor Antagonists

Exploiting the 2-(1,3,4,9-tetrahydropyrano[3,4- b]indol-1-yl)acetic Acid Scaffold to Generate COXTRANs: A New Class of Dual Cyclooxygenase Inhibitors-Thromboxane Receptor Antagonists

  • J Med Chem. 2025 Nov 13;68(21):23185-23219. doi: 10.1021/acs.jmedchem.5c02068.
Federica Blua 1,  Francesca Boccato 1,  Carola Buccellati 2,  Patrizia Risè 2,  Silvia Barbieri 3,  Laura Castiglioni 2,  Annika Balzulat 4,  Barbara Rolando 1,  Elisabetta Marini 1,  Marta Balestra 1,  Maria Luisa Introvigne 1,  Marta Giorgis 1,  Luigi Sironi 2,  Stefania Tacconelli 5 6,  Kerstin Hiesinger 7,  Paola Patrignani 5 6,  Achim Schmidtko 4,  Dieter Steinhilber 7,  Ewgenij Proschak 7,  Angelo Sala 2,  G Enrico Rovati 2,  Massimo Bertinaria 1
Affiliations

Affiliations

  • 1 Department of Drug Science and Technology, University of Turin, Via P. Giuria 9, Turin 10125, Italy.
  • 2 Department of Pharmaceutical Sciences, University of Milan, Milan 20122, Italy.
  • 3 Centro Cardiologico Monzino IRCCS, Milan 20138, Italy.
  • 4 Institute of Pharmacology and Clinical Pharmacy, Goethe University, Max-von-Laue-Str. 9, Frankfurt am Main D-60438, Germany.
  • 5 Department of Neuroscience, Imaging and Clinical Sciences, "G. d'Annunzio" University, Chieti 66100, Italy.
  • 6 Laboratory of Systems Pharmacology and Translational Therapies, Center for Advanced Studies and Technology (CAST), ″G. d'Annunzio″ University, Chieti 66100, Italy.
  • 7 Institute of Pharmaceutical Chemistry, Goethe-University, Max-von-Laue-Str. 9, Frankfurt am Main D-60438, Germany.
PMID: 41124679 DOI: 10.1021/acs.jmedchem.5c02068
Abstract

The use of traditional nonsteroidal anti-inflammatory drugs (NSAIDs) and coxibs is effective for the treatment of inflammatory pain and chronic inflammatory conditions. However, their use is associated with enhanced risk of cardiovascular toxicity and thrombotic events, particularly for the latter. The vascular side effects of these drugs could be mitigated by pharmacological inhibition of the thromboxane A2 receptor (TP). Here we describe the development of a new class of dual cyclooxygenase (COX) inhibitors/thromboxane receptor antagonists (COXTRANs) based on the 2-(1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid scaffold. The in vitro evaluation of 50 newly synthesized compounds resulted in a set of well-balanced compounds exhibiting nanomolar activity on both COX-2 and TP receptor. Further studies in human whole blood and physicochemical profiling allowed the prioritization of 51 (CXT29) as a suitable candidate for in vivo studies. Compound 51, after oral administration, was able to prevent TP receptor-mediated platelet aggregation and to reduce inflammatory pain in mice.

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