Synthesis and Molecular Modelling Studies of New 1,3-Diaryl-5-Oxo-Proline Derivatives as Endothelin Receptor Ligands
Sebastiano Intagliata,
Mohamed A. Helal,
Luisa Materia,
Valeria Pittalà,
Loredana Salerno,
Agostino Marrazzo,
Alfredo Cagnotto,
Mario Salmona,
Maria N. Modica,
Giuseppe Romeo
Affiliations
Sebastiano Intagliata
Department of Drug Sciences, University of Catania, Viale A. Doria 6, 95125 Catania, Italy
Mohamed A. Helal
University of Science and Technology, Biomedical Sciences Program, Zewail City of Science and Technology, October Gardens, 6th of October, Giza 12578, Egypt
Luisa Materia
Department of Drug Sciences, University of Catania, Viale A. Doria 6, 95125 Catania, Italy
Valeria Pittalà
Department of Drug Sciences, University of Catania, Viale A. Doria 6, 95125 Catania, Italy
Loredana Salerno
Department of Drug Sciences, University of Catania, Viale A. Doria 6, 95125 Catania, Italy
Agostino Marrazzo
Department of Drug Sciences, University of Catania, Viale A. Doria 6, 95125 Catania, Italy
Alfredo Cagnotto
Istituto di Ricerche Farmacologiche “Mario Negri”, IRCCS. Via Mario Negri, 2, 20156 Milano, Italy
Mario Salmona
Istituto di Ricerche Farmacologiche “Mario Negri”, IRCCS. Via Mario Negri, 2, 20156 Milano, Italy
Maria N. Modica
Department of Drug Sciences, University of Catania, Viale A. Doria 6, 95125 Catania, Italy
Giuseppe Romeo
Department of Drug Sciences, University of Catania, Viale A. Doria 6, 95125 Catania, Italy
The synthesis of seventeen new 1,3-diaryl-5-oxo-proline derivatives as endothelin receptor (ETR) ligands is described. The structural configuration of the new molecules was determined by analyzing selected signals in proton NMR spectra. In vitro binding assays of the human ETA and ETB receptors allowed us to identify compound 31h as a selective ETAR ligand. The molecular docking of the selected compounds and the ETA antagonist atrasentan in the ETAR homology model provided insight into the structural elements required for the affinity and the selectivity of the ETAR subtype.
