Institute of Molecular Biology and Tumor Research (IMT), Philipps University, Emil-Mannkopff-Strasse 2, 35033 Marburg, Germany.
J Med Chem. 2012 Mar 22;55(6):2858-68. doi: 10.1021/jm2017122. Epub 2012 Mar 8.
The ligand-regulated nuclear receptor peroxisome proliferator-activated receptor β/δ (PPARβ/δ) is a potential pharmacological target due to its role in disease-related biological processes. We used TR-FRET-based competitive ligand binding and coregulator interaction assays to screen 2693 compounds of the Open Chemical Repository of the NCI/NIH Developmental Therapeutics Program for inhibitory PPARβ/δ ligands. One compound, (Z)-3-(4-dimethylamino-phenyl)-2-phenyl-acrylonitrile, was used for a systematic SAR study. This led to the design of derivative 37, (Z)-2-(2-bromophenyl)-3-{[4-(1-methyl-piperazine)amino]phenyl}acrylonitrile (DG172), a novel PPARβ/δ-selective ligand showing high binding affinity (IC(50) = 27 nM) and potent inverse agonistic properties. 37 selectively inhibited the agonist-induced activity of PPARβ/δ, enhanced transcriptional corepressor recruitment, and down-regulated transcription of the PPARβ/δ target gene Angptl4 in mouse myoblasts (IC(50) = 9.5 nM). Importantly, 37 was bioavailable after oral application to mice with peak plasma levels in the concentration range of its maximal inhibitory potency, suggesting that 37 will be an invaluable tool to elucidate the functions and therapeutic potential of PPARβ/δ.
配体调控的核受体过氧化物酶体增殖物激活受体β/δ（PPARβ/δ）在疾病相关的生物过程中发挥作用，因此成为一种有潜力的药物靶点。我们使用基于时间分辨荧光共振能量转移（TR-FRET）的竞争性配体结合和共激活因子相互作用检测方法，从 NCI/NIH 发育治疗学计划的开放化学库中筛选了 2693 种化合物，寻找抑制 PPARβ/δ 的配体。一种名为（Z）-3-(4-二甲基氨基-苯基)-2-苯基丙烯腈的化合物被用于进行系统的 SAR 研究。在此基础上设计出了衍生物 37，（Z）-2-(2-溴苯基)-3-｛[4-(1-甲基-哌嗪)氨基]苯基｝丙烯腈（DG172），这是一种新型的 PPARβ/δ 选择性配体，具有高结合亲和力（IC50=27 nM）和有效的反向激动特性。37 可选择性抑制激动剂诱导的 PPARβ/δ 活性，增强转录共抑制因子募集，并下调小鼠成肌细胞中 PPARβ/δ 靶基因 Angptl4 的转录（IC50=9.5 nM）。重要的是，37 经口服给予小鼠后具有生物利用度，在其最大抑制效力的浓度范围内达到血浆峰值水平，这表明 37 将成为阐明 PPARβ/δ 功能和治疗潜力的宝贵工具。
