2011 Sep 16;2(11):793-7. doi: 10.1021/ml200091q. eCollection 2011.
Discovery of Potent Dual PPARα Agonists/CB1 Ligands.
Pérez-Fernández R1, Fresno N1, Macías-González M2, Elguero J1, Decara J3, Girón R4, Rodríguez-Álvarez A4, Martín MI4, Rodríguez de Fonseca F3, Goya P1.
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 cannabinoidreceptor 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
- PMID:
24936232
[PubMed]
