title: Discovery of novel non-cyclam polynitrogenated CXCR4 coreceptor inhibitors.
abstract: HIV cell fusion and entry have been validated as targets for therapeutic intervention against infection. Bicyclams were the first low-molecular-weight compounds to show specific interaction with CXCR4. The most potent bicyclam was AMD3100, in which the two cyclam moieties are tethered by a 1,4-phenylenebis(methylene) bridge. It was withdrawn from clinical trials owing to its lack of oral bioavailability and cardiotoxicity. We have designed a combinatorial library of non-cyclam polynitrogenated compounds by preserving the main features of AMD3100. At least two nitrogen atoms on each side of the p-phenylene moiety, one in the benzylic position and the other(s) in the heterocyclic system were maintained, and the distances between them were similar to the nitrogen atom distances in cyclam. A selection of diverse compounds from this library were prepared, and their in vitro activity was tested in cell cultures against HIV strains. This led to the identification of novel potent CXCR4 coreceptor inhibitors without cytotoxicity at the tested concentrations.
authors.affiliation: Grup d'Enginyeria Molecular, Institut Químic de Sarrià, Universitat Ramon Llull, Via Augusta 390, 08017 Barcelona, Spain.
authors.forename: Sofia
authors.initials: S
authors.lastname: Pettersson
authors.forename: Violeta I
authors.initials: VI
authors.lastname: Pérez-Nueno
authors.forename: Laia
authors.initials: L
authors.lastname: Ros-Blanco
authors.forename: Raimon
authors.initials: R
authors.lastname: Puig de La Bellacasa
authors.forename: María Obdulia
authors.initials: MO
authors.lastname: Rabal
authors.forename: Xavier
authors.initials: X
authors.lastname: Batllori
authors.forename: Bonaventura
authors.initials: B
authors.lastname: Clotet
authors.forename: Imma
authors.initials: I
authors.lastname: Clotet-Codina
authors.forename: Mercedes
authors.initials: M
authors.lastname: Armand-Ugón
authors.forename: José
authors.initials: J
authors.lastname: Esté
authors.forename: José I
authors.initials: JI
authors.lastname: Borrell
authors.forename: Jordi
authors.initials: J
authors.lastname: Teixidó
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology; D001596:Benzylamines; D002478:Cells, Cultured; D000080027:Cyclams; D015195:Drug Design; D006571:Heterocyclic Compounds / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D051379:Mice; D008956:Models, Chemical; D017434:Protein Structure, Tertiary; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D000998:Antiviral Agents; D001596:Benzylamines; D000080027:Cyclams; D006571:Heterocyclic Compounds; D019718:Receptors, CXCR4; C088327:plerixafor