强效双重PPARα激动剂/CB1配体的发现。
Discovery of Potent Dual PPARα Agonists/CB1 Ligands.
作者信息
Pérez-Fernández Ruth, Fresno Nieves, Macías-González Manuel, Elguero José, Decara Juan, Girón Rocío, Rodríguez-Álvarez Ana, Martín María Isabel, Rodríguez de Fonseca Fernando, Goya Pilar
机构信息
Instituto de Química Médica , IQM-CSIC, Juan de la Cierva 3, 28006, Madrid, Spain.
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.
出版信息
ACS Med Chem Lett. 2011 Sep 16;2(11):793-7. doi: 10.1021/ml200091q. eCollection 2011 Nov 10.
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.
摘要
这封信描述了靶向大麻素和过氧化物酶体增殖物激活受体（PPAR）的双配体的合成及其体外和体内评价。这些化合物是通过将贝特类药物的药效基团与大麻素受体拮抗剂二芳基吡唑利莫那班融合而获得的。它们是对PPARα和大麻素受体均具有纳摩尔亲和力的双化合物的首个实例。此外，先导化合物2被证明对CB1具有选择性。出乎意料的是，所测试的酚类中间体具有同等效力（化合物1与2相比）甚至更强效（化合物3与4相比）。这一发现为设计新的双配体开辟了道路。
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