Synthesis of arylpiperazine derivatives as protease activated receptor 1 antagonists and their evaluation as antiproliferative agents

Andrea Ilaria Zotti, Elena Di Gennaro, Angela Corvino, Francesco Frecentese, Elisa Magli, Elisa Perissutti, Giuseppe Cirino, Fiorentina Roviezzo, Manuela Terranova-Barberio, Federica Iannelli, Giuseppe Caliendo, Vincenzo Santagada, Ferdinando Fiorino, Alfredo Budillon, Beatrice Severino

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Protease activated receptor-1 (PAR1) is a G-coupled receptor activated by α-thrombin and other proteases. Several reports have demonstrated the PAR1 involvement in tumorigenesis and tumor progression. In order to investigate on potential use of PAR1 antagonists as antiproliferative agents. Aims: We have identified a series of arylpiperazine derivatives acting as PAR1 antagonists; the selected molecules have been evaluated for their antiproliferative properties. Method: All the compounds inhibited the growth of a panel of cell lines expressing PAR1; two of them, compounds 13 and 15, were able to inhibit, in a dose dependent manner, the growth of the selected cell lines with the lowest IC50 values, and were further characterized to define the mechanism responsible for the observed antiproliferative effect. Result: This study directed us to the identification of two interesting leads that may help to further validate PAR1 as an important therapeutic target for cancer treatment.

Original languageEnglish
Pages (from-to)973-981
Number of pages9
JournalAnti-Cancer Agents in Medicinal Chemistry
Volume17
Issue number7
DOIs
Publication statusPublished - 2017

Keywords

  • Antagonists
  • Antiproliferative agents
  • Arylpiperazines
  • Protease activated receptor-1

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology
  • Cancer Research

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