1. Academic Validation
  2. Discovery of Potent Dual PPARα Agonists/CB1 Ligands

Discovery of Potent Dual PPARα Agonists/CB1 Ligands

  • ACS Med Chem Lett. 2011 Sep 16;2(11):793-7. doi: 10.1021/ml200091q.
Ruth Pérez-Fernández 1 Nieves Fresno 1 Manuel Macías-González 2 José Elguero 1 Juan Decara 3 Rocío Girón 4 Ana Rodríguez-Álvarez 4 María Isabel Martín 4 Fernando Rodríguez de Fonseca 3 Pilar Goya 1
Affiliations

Affiliations

  • 1 Instituto de Química Médica , IQM-CSIC, Juan de la Cierva 3, 28006, Madrid, Spain.
  • 2 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.
  • 3 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.
  • 4 Departamento de Farmacología y Nutrición, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos , Avda. Atenas S/N, 28922 Alcorcón, Madrid, Spain.
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.

Keywords

Dual ligands; PPARα; cannabinoids; fibrates; neuroprotective; rimonabant.

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