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

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journal contribution
posted on 16.02.2021, 19:54 by José Luis Díaz, Félix Cuevas, Gonzalo Pazos, Paula Álvarez-Bercedo, Ana I. Oliva, M. Ángeles Sarmentero, Daniel Font, Agustín Jiménez-Aquino, María Morón, Adriana Port, Rosalía Pascual, Albert Dordal, Enrique Portillo-Salido, Raquel F. Reinoso, José Miguel Vela, Carmen Almansa
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.