Synthesis of Arylpiperazine Derivatives as Protease Activated Receptor 1 Antagonists and Their Evaluation as Antiproliferative Agents.
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.


OBJECTIVE
We have identified a series of arylpiperazine derivatives acting as PAR1 antagonists; the selected molecules have been evaluated for their antiproliferative properties.


METHODS
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.


RESULTS
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.
Unita di Farmacologia Sperimentale, "Istituto Nazionale dei Tumori Fondazione G. Pascale" -IRCCS - Via M. Semmola, 80131 Naples, Italy.
Andrea Ilaria
AI
Zotti
Unita di Farmacologia Sperimentale, "Istituto Nazionale dei Tumori Fondazione G. Pascale" -IRCCS - Via M. Semmola, 80131 Naples, Italy.
Elena
E
Di Gennaro
Dipartimento di Farmacia, Università degli Studi di Napoli «Federico II», Via D. Montesano, 49, 80131, Napoli, Italy.
Angela
A
Corvino
Dipartimento di Farmacia, Università degli Studi di Napoli «Federico II», Via D. Montesano, 49, 80131, Napoli, Italy.
Francesco
F
Frecentese
Dipartimento di Farmacia, Università degli Studi di Napoli «Federico II», Via D. Montesano, 49, 80131, Napoli, Italy.
Elisa
E
Magli
Dipartimento di Farmacia, Università degli Studi di Napoli «Federico II», Via D. Montesano, 49, 80131, Napoli, Italy.
Elisa
E
Perissutti
Dipartimento di Farmacia, Università degli Studi di Napoli «Federico II», Via D. Montesano, 49, 80131, Napoli, Italy.
Giuseppe
G
Cirino
Dipartimento di Farmacia, Università degli Studi di Napoli «Federico II», Via D. Montesano, 49, 80131, Napoli, Italy.
Fiorentina
F
Roviezzo
Unita di Farmacologia Sperimentale, "Istituto Nazionale dei Tumori Fondazione G. Pascale" -IRCCS - Via M. Semmola, 80131 Naples, Italy.
Manuela
M
Terranova-Barberio
Unita di Farmacologia Sperimentale, "Istituto Nazionale dei Tumori Fondazione G. Pascale" -IRCCS - Via M. Semmola, 80131 Naples, Italy.
Federica
F
Iannelli
Dipartimento di Farmacia, Università degli Studi di Napoli «Federico II», Via D. Montesano, 49, 80131, Napoli, Italy.
Giuseppe
G
Caliendo
Dipartimento di Farmacia, Università degli Studi di Napoli «Federico II», Via D. Montesano, 49, 80131, Napoli, Italy.
Vincenzo
V
Santagada
Dipartimento di Farmacia, Università degli Studi di Napoli «Federico II», Via D. Montesano, 49, 80131, Napoli, Italy.
Ferdinando
F
Fiorino
Unita di Farmacologia Sperimentale, "Istituto Nazionale dei Tumori Fondazione G. Pascale" -IRCCS - Via M. Semmola, 80131 Naples, Italy.
Alfredo
A
Budillon
Department of Pharmacy, University of Naples "Federico II", Via D. Montesano, 49 - 80131- Napoli, Italy.
Beatrice
B
Severino
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D006801:Humans; D008297:Male; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D017208:Rats, Wistar; D044463:Receptor, PAR-1 / Q000378:metabolism; D010975:Platelet Aggregation Inhibitors
D000970:Antineoplastic Agents; D010879:Piperazines; D044463:Receptor, PAR-1; D010975:Platelet Aggregation Inhibitors
Antagonists; antiproliferative agents; arylpiperazines; protease activated receptor-1