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

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

  • J Med Chem. 2021 Feb 25;64(4):2167-2185. doi: 10.1021/acs.jmedchem.0c01867.
José Luis Díaz 1,  Félix Cuevas 2,  Gonzalo Pazos 2,  Paula Álvarez-Bercedo 2,  Ana I Oliva 2,  M Ángeles Sarmentero 2,  Daniel Font 2,  Agustín Jiménez-Aquino 2,  María Morón 2,  Adriana Port 1,  Rosalía Pascual 1,  Albert Dordal 1,  Enrique Portillo-Salido 1,  Raquel F Reinoso 1,  José Miguel Vela 1,  Carmen Almansa 1
Affiliations

Affiliations

  • 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.
PMID: 33591743 DOI: 10.1021/acs.jmedchem.0c01867
Abstract

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.

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