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Discovery of an oxybenzylglycine based peroxisome proliferator activated receptor alpha selective agonist 2-((3-((2-(4-chlorophenyl)-5-methyloxazol-4-yl)methoxy)benzyl)(methoxycarbonyl)amino)acetic acid (BMS-687453).发现一种基于氧苯甲基甘氨酸的过氧化物酶体增殖物激活受体 α 选择性激动剂 2-((3-((2-(4-氯苯基)-5-甲基恶唑-4-基)甲氧基)苄基)(甲氧基羰基)氨基)乙酸（BMS-687453）。
J Med Chem. 2010 Apr 8;53(7):2854-64. doi: 10.1021/jm9016812.
2
Cannabinoid activation of peroxisome proliferator-activated receptors: potential for modulation of inflammatory disease.大麻素激活过氧化物酶体增殖物激活受体：调节炎症性疾病的潜力。
Immunobiology. 2010 Aug;215(8):611-6. doi: 10.1016/j.imbio.2009.09.007. Epub 2009 Oct 14.
3
Cannabinoid activation of PPAR alpha; a novel neuroprotective mechanism.大麻素对过氧化物酶体增殖物激活受体α的激活作用；一种新型神经保护机制。
Br J Pharmacol. 2007 Nov;152(5):734-43. doi: 10.1038/sj.bjp.0707478. Epub 2007 Oct 1.
4
The cannabinoid CB1 receptor antagonist SR141716A (Rimonabant) enhances the metabolic benefits of long-term treatment with oleoylethanolamide in Zucker rats.大麻素CB1受体拮抗剂SR141716A（利莫那班）可增强油酸乙醇酰胺对 Zucker 大鼠长期治疗的代谢益处。
Neuropharmacology. 2008 Jan;54(1):226-34. doi: 10.1016/j.neuropharm.2007.03.007. Epub 2007 Mar 24.
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Synergistic antinociception by the cannabinoid receptor agonist anandamide and the PPAR-alpha receptor agonist GW7647.大麻素受体激动剂花生四烯乙醇胺与过氧化物酶体增殖物激活受体-α受体激动剂GW7647的协同抗伤害感受作用。
Eur J Pharmacol. 2007 Jul 2;566(1-3):117-9. doi: 10.1016/j.ejphar.2007.03.007. Epub 2007 Mar 19.
6
Novel sulfamide analogs of oleoylethanolamide showing in vivo satiety inducing actions and PPARalpha activation.具有体内饱腹感诱导作用和过氧化物酶体增殖物激活受体α（PPARα）激活作用的新型油酰乙醇胺磺酰胺类似物。
J Med Chem. 2007 Jan 25;50(2):389-93. doi: 10.1021/jm0601102.
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The physicochemical challenges of designing multiple ligands.设计多种配体时的物理化学挑战。
J Med Chem. 2006 Aug 10;49(16):4961-70. doi: 10.1021/jm0603015.
8
Deorphanization of a G protein-coupled receptor for oleoylethanolamide and its use in the discovery of small-molecule hypophagic agents.一种针对油酰乙醇胺的G蛋白偶联受体的去孤儿化及其在小分子食欲抑制剂发现中的应用。
Cell Metab. 2006 Mar;3(3):167-75. doi: 10.1016/j.cmet.2006.02.004.
9
The bioassay of cannabinoids using the mouse isolated vas deferens.使用小鼠离体输精管对大麻素进行生物测定。
Methods Mol Med. 2006;123:191-207. doi: 10.1385/1-59259-999-0:191.
10
PPARs: therapeutic targets for metabolic disease.过氧化物酶体增殖物激活受体：代谢性疾病的治疗靶点
Trends Pharmacol Sci. 2005 May;26(5):244-51. doi: 10.1016/j.tips.2005.03.003.

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.

DOI:10.1021/ml200091q
PMID:24936232
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4056814/
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。