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


Díaz JL(1), Cuevas F(2), Pazos G(2), Álvarez-Bercedo P(2), Oliva AI(2), Sarmentero MÁ(2), Font D(2), Jiménez-Aquino A(2), Morón M(2), Port A(1), Pascual R(1), Dordal A(1), Portillo-Salido E(1), Reinoso RF(1), Vela JM(1), Almansa C(1).
Author information:
(1)ESTEVE Pharmaceuticals, Torre Esteve, Passeig de la Zona Franca, 109, 08038 Barcelona, Spain.
(2)Institute of Chemical Research of Catalonia
(ICIQ), Barcelona Institute of Science and Technology, Av. Països Catalans 16, 43007 Tarragona, Spain.


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.