title: A Versatile Approach to CF3 -Containing 2-Pyrrolidones by Tandem Michael Addition-Cyclization: Exemplification in the Synthesis of Amidine Class BACE1 Inhibitors.
abstract: The synthesis of new fluorinated pyrrolidones starting from unprotected amino esters and amino nitriles through a Michael addition-lactamization sequence is described. The resulting CF3 -containing building blocks, bearing a quaternary stereogenic center adjacent to the fluorinated group, have been converted into amino pyrrolidines that display potent β-secretase 1 (BACE1) inhibitory activity. This work constitutes an example of selective fluorination as a valid strategy for the modulation of physicochemical and biological properties of lead compounds in drug discovery.
authors.affiliation: Departamento de Química Orgánica, Universidad de Valencia, 46100-Burjassot (Spain). natalia.mateu@uv.es.|Laboratorio de Moléculas Orgánicas, Centro de Investigación Príncipe Felipe (CIPF), 46012-Valencia (Spain). natalia.mateu@uv.es.
authors.forename: Natalia
authors.initials: N
authors.lastname: Mateu
authors.affiliation: Neuroscience Medicinal Chemistry Department, Janssen Research and Development, E-45007-Toledo (Spain).|Departamento de Química y Bioquímica, Facultad de Farmacia Universidad CEU San Pablo, Urbanización Monteprincipe Ctra., Boadilla del Monte Km 5,3, 28668 Madrid (Spain).
authors.forename: Myriam
authors.initials: M
authors.lastname: Ciordia
authors.affiliation: Neuroscience Medicinal Chemistry Department, Janssen Research and Development, E-45007-Toledo (Spain). odelgad1@its.jnj.com.
authors.forename: Oscar
authors.initials: O
authors.lastname: Delgado
authors.affiliation: Departamento de Química Orgánica, Universidad de Valencia, 46100-Burjassot (Spain).|Laboratorio de Moléculas Orgánicas, Centro de Investigación Príncipe Felipe (CIPF), 46012-Valencia (Spain).
authors.forename: María
authors.initials: M
authors.lastname: Sánchez-Roselló
authors.affiliation: Neuroscience Medicinal Chemistry Department, Janssen Research and Development, E-45007-Toledo (Spain).
authors.forename: Andrés A
authors.initials: AA
authors.lastname: Trabanco
authors.affiliation: Neuroscience Medicinal Chemistry Department, Janssen Research and Development, E-45007-Toledo (Spain).
authors.forename: Michiel
authors.initials: M
authors.lastname: Van Gool
authors.affiliation: Neuroscience Medicinal Chemistry Department, Janssen Research and Development, E-45007-Toledo (Spain).
authors.forename: Gary
authors.initials: G
authors.lastname: Tresadern
authors.affiliation: Neuroscience Medicinal Chemistry Department, Janssen Research and Development, E-45007-Toledo (Spain).
authors.forename: Laura
authors.initials: L
authors.lastname: Pérez-Benito
authors.affiliation: Departamento de Química Orgánica, Universidad de Valencia, 46100-Burjassot (Spain). santos.fustero@uv.es.|Laboratorio de Moléculas Orgánicas, Centro de Investigación Príncipe Felipe (CIPF), 46012-Valencia (Spain). santos.fustero@uv.es.
authors.forename: Santos
authors.initials: S
authors.lastname: Fustero
mesh_terms: D000578:Amidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D003500:Cyclization; D055808:Drug Discovery; D006845:Hydrocarbons, Fluorinated / Q000737:chemistry* / Q000494:pharmacology*; D015394:Molecular Structure; D011760:Pyrrolidinones / Q000737:chemistry* / Q000494:pharmacology*; D013237:Stereoisomerism
chemical_list: D000578:Amidines; D006845:Hydrocarbons, Fluorinated; D011760:Pyrrolidinones; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C028537:2-pyrrolidone
keywords: cyclization; drug discovery; enzymes; fluorine; inhibitors