title: Discovery of Potent Dual PPARα Agonists/CB1 Ligands.
abstract: This letter describes the synthesis and in vitro and in vivo evaluation of dual ligands targeting the cannabinoid and peroxisome proliferator-activated receptors (PPAR). These compounds were obtained from fusing the pharmacophores of fibrates and the diarylpyrazole rimonabant, a cannabinoid receptor antagonist. They are the first examples of dual compounds with nanomolar affinity for both PPARα and cannabinoid receptors. Besides, lead compound 2 proved to be CB1 selective. Unexpectedly, the phenol intermediates tested were equipotent (compound 1 as compared to 2) or even more potent (compound 3 as compared with 4). This discovery opens the way to design new dual ligands.
authors.affiliation: Instituto de Química Médica , IQM-CSIC, Juan de la Cierva 3, 28006, Madrid, Spain.
authors.forename: Ruth
authors.initials: R
authors.lastname: Pérez-Fernández
authors.affiliation: Instituto de Química Médica , IQM-CSIC, Juan de la Cierva 3, 28006, Madrid, Spain.
authors.forename: Nieves
authors.initials: N
authors.lastname: Fresno
authors.affiliation: Servicio de Endocrinología Nutrición, Hospital Virgen de la Victoria (Fundación IMABIS), Málaga, CIBER Fisiopatología de la Obesidad y Nutrición , CB06/03, Instituto de Salud Carlos III, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Macías-González
authors.affiliation: Instituto de Química Médica , IQM-CSIC, Juan de la Cierva 3, 28006, Madrid, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Elguero
authors.affiliation: Fundación Hospital Carlos Haya , Avda. Carlos Haya 82, 29010, Málaga, Spain ; CIBER OBN (Centro de Investigación Biomédica en Red de la Fisiopatología de la Obesidad y Nutrición) , Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación, 28029 Madrid, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Decara
authors.affiliation: Departamento de Farmacología y Nutrición, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos , Avda. Atenas S/N, 28922 Alcorcón, Madrid, Spain.
authors.forename: Rocío
authors.initials: R
authors.lastname: Girón
authors.affiliation: Departamento de Farmacología y Nutrición, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos , Avda. Atenas S/N, 28922 Alcorcón, Madrid, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Rodríguez-Álvarez
authors.affiliation: Departamento de Farmacología y Nutrición, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos , Avda. Atenas S/N, 28922 Alcorcón, Madrid, Spain.
authors.forename: María Isabel
authors.initials: MI
authors.lastname: Martín
authors.affiliation: Fundación Hospital Carlos Haya , Avda. Carlos Haya 82, 29010, Málaga, Spain ; CIBER OBN (Centro de Investigación Biomédica en Red de la Fisiopatología de la Obesidad y Nutrición) , Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación, 28029 Madrid, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Rodríguez de Fonseca
authors.affiliation: Instituto de Química Médica , IQM-CSIC, Juan de la Cierva 3, 28006, Madrid, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Goya
keywords: Dual ligands; PPARα; cannabinoids; fibrates; neuroprotective; rimonabant