Exploiting the 2-(1,3,4,9-tetrahydropyrano[3,4- <i>b</i> ]indol-1-yl)acetic Acid Scaffold to Generate COXTRANs: A New Class of Dual Cyclooxygenase Inhibitors-Thromboxane Receptor Antagonists
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 A<sub>2</sub> 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-<i>b</i>]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 <b>51</b> (CXT29) as a suitable candidate for in vivo studies. Compound <b>51</b>, after oral administration, was able to prevent TP receptor-mediated platelet aggregation and to reduce inflammatory pain in mice.
Authors
- Ewgenij Proschak (ORCID: https://orcid.org/0000-0003-1961-1859)
- Kerstin Hiesinger (ORCID: https://orcid.org/0000-0001-5458-816X)
- Patrizia Risé (ORCID: https://orcid.org/0000-0002-7564-3508)
- Achim Schmidtko (ORCID: https://orcid.org/0000-0001-7270-5075)
- Angelo Sala (ORCID: https://orcid.org/0000-0001-9290-0257)
- Elisabetta Marini (ORCID: https://orcid.org/0000-0001-8779-8745)
- Carola Buccellati
- Luigi Sironi (ORCID: https://orcid.org/0000-0002-4738-3454)
- G. Enrico Rovati (ORCID: https://orcid.org/0000-0002-8788-9783)
- Laura Castiglioni (ORCID: https://orcid.org/0000-0002-0772-3231)
- Barbara Rolando (ORCID: https://orcid.org/0000-0001-6138-1503)
- Massimo Bertinaria (ORCID: https://orcid.org/0000-0002-2533-5830)
- Michael Balestra (ORCID: https://orcid.org/0009-0006-9068-5817)
- Maria Luisa Introvigne (ORCID: https://orcid.org/0000-0002-7670-216X)
- Stefania Tacconelli (ORCID: https://orcid.org/0000-0003-4907-1822)
- Annika Balzulat
- Marta Giorgis (ORCID: https://orcid.org/0000-0002-3282-1220)
- Paola Patrignani (ORCID: https://orcid.org/0000-0003-1419-2691)
- Dieter Steinhilber (ORCID: https://orcid.org/0000-0001-8905-5208)
- Silvia Stella Barbieri (ORCID: https://orcid.org/0000-0002-7486-2637)
- Federica Blua (ORCID: https://orcid.org/0000-0002-0306-9543)
- Francesca Boccato (ORCID: https://orcid.org/0009-0001-3978-3490)
Institutions
- Goethe University Frankfurt (DE)
- University of Milan (IT)
- University of Chieti-Pescara (IT)
- Centro Cardiologico Monzino (IT)
- Center for Translational Molecular Medicine (NL)
- Ospedale SS. Annunziata (IT)
- University of Turin (IT)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-10-22
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c02068
- Citations
- 1
- Primary Topic
- Inflammatory mediators and NSAID effects
- Type
- article
- Field-Weighted Citation Impact
- 1.39