title: Design and synthesis of 4,5,6,7-tetrahydro-1H-1,2-diazepin-7-one derivatives as a new series of Phosphodiesterase 4 (PDE4) inhibitors.
abstract: Phosphodiesterase 4 (PDE4) inhibitors have attractive therapeutic potential in respiratory, inflammatory, metabolic and CNS disorders. The present work details the design, chemical exploration and biological profile of a novel PDE4 inhibitor chemotype. A diazepinone ring was identified as an under-represented heterocyclic system fulfilling a set of PDE4 structure-based design hypotheses. Rapid exploration of the structure activity relationships for the series was enabled by robust and scalable two/three-steps parallel chemistry protocols. The resulting compounds demonstrated PDE4 inhibitory activity in cell free and cell-based assays comparable to the Zardaverine control used, suggesting potential avenues for their further development.
authors.affiliation: Department of Pharmacy, University of Genoa, Viale Benedetto XV n. 3, 16132 Genoa, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Guariento
authors.affiliation: Medicinal Chemistry, Taros Chemicals GmbH & Co. KG, Emil-Figge-Str. 76a, 44227 Dortmund, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Karawajczyk
authors.affiliation: Medicinal Chemistry, Taros Chemicals GmbH & Co. KG, Emil-Figge-Str. 76a, 44227 Dortmund, Germany.
authors.forename: James A
authors.initials: JA
authors.lastname: Bull
authors.affiliation: Pharmacology Toxicology Department, Chiesi Farmaceutici S.p.A., Nuovo Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy.
authors.forename: Gessica
authors.initials: G
authors.lastname: Marchini
authors.affiliation: Medicinal Chemistry, Taros Chemicals GmbH & Co. KG, Emil-Figge-Str. 76a, 44227 Dortmund, Germany.
authors.forename: Martyna
authors.initials: M
authors.lastname: Bielska
authors.affiliation: Medicinal Chemistry, Taros Chemicals GmbH & Co. KG, Emil-Figge-Str. 76a, 44227 Dortmund, Germany.
authors.forename: Xenia
authors.initials: X
authors.lastname: Iwanowa
authors.affiliation: Department of Pharmacy, University of Genoa, Viale Benedetto XV n. 3, 16132 Genoa, Italy.
authors.forename: Olga
authors.initials: O
authors.lastname: Bruno
authors.affiliation: Department of Pharmacy, University of Genoa, Viale Benedetto XV n. 3, 16132 Genoa, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Fossa
authors.affiliation: Medicinal Chemistry, Taros Chemicals GmbH & Co. KG, Emil-Figge-Str. 76a, 44227 Dortmund, Germany. Electronic address: fabrizio.giordanetto@deshawresearch.com.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Giordanetto
mesh_terms: D001381:Azepines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D015394:Molecular Structure; D058988:Phosphodiesterase 4 Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis
chemical_list: D001381:Azepines; D008070:Lipopolysaccharides; D058988:Phosphodiesterase 4 Inhibitors; D014409:Tumor Necrosis Factor-alpha; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4
keywords: Compound library; Diazepinone derivatives; PDE4 inhibitors; Phosphodiesterase 4