Bicyclic Diazepinones as Dual Ligands of the α2δ‑1 Subunit of Voltage-Gated Calcium Channels and the Norepinephrine Transporter

• Published in: Journal of medicinal chemistry Vol. 64; no. 4; pp. 2167 - 2185
• Main Authors: Díaz, José Luis, Cuevas, Félix, Pazos, Gonzalo, Álvarez-Bercedo, Paula, Oliva, Ana I, Sarmentero, M. Ángeles, Font, Daniel, Jiménez-Aquino, Agustín, Morón, María, Port, Adriana, Pascual, Rosalía, Dordal, Albert, Portillo-Salido, Enrique, Reinoso, Raquel F, Vela, José Miguel, Almansa, Carmen
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 25.02.2021
• Subjects: Animals; Azepines - chemical synthesis; Azepines - metabolism; Azepines - pharmacology; Calcium Channels - metabolism; CHO Cells; Cricetulus; HEK293 Cells; Heterocyclic Compounds, 2-Ring - chemical synthesis; Heterocyclic Compounds, 2-Ring - metabolism; Heterocyclic Compounds, 2-Ring - pharmacology; Humans; Ligands; Molecular Docking Simulation; Molecular Structure; Norepinephrine Plasma Membrane Transport Proteins - metabolism; Protein Binding; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.0c01867

The synthesis and pharmacological activity of a new series of bicyclic diazepinones with dual activity toward the α2δ-1 subunit of voltage-gated calcium channels (Cavα2δ-1) and the norepinephrine transporter (NET) are reported. Exploration of the positions amenable for substitution on a nonaminoacidic Cavα2δ-1 scaffold allowed the identification of favorable positions for the attachment of NET pharmacophores. Among the patterns explored, attachment of the 2-ethylamino-9-methyl-6-phenyl-6,7,8,9-tetrahydro-5H-pyrimido­[4,5-e]­[1,4]­diazepin-5-one framework to the meta-position of the phenyl ring of the 3-methylamino-1-phenylpropoxy and 3-methylamino-1-thiophenylpropoxy moieties provided dual compounds with excellent NET functionality. Alternative bicyclic frameworks were also explored, and some lead molecules were identified, which showed a balanced dual profile and exhibited good ADMET properties.