We describe the parallel synthesis of novel analogs of GW0742, a peroxisome proliferator-activated receptor δ (PPARδ) agonist. For that purpose, modified reaction conditions were applied, such as a solid-phase palladium-catalyzed Suzuki coupling. In addition, tetrazole-based compounds were generated as a bioisostere for carboxylic acid-containing ligand GW0742. The new compounds were investigated for their ability to activate PPARδ mediated transcription and their cross-reactivity with the vitamin D receptor (VDR), another member of the nuclear receptor superfamily. We identified many potent PPARδ agonists that were less toxic than GW0742, where ∼65 of the compounds synthesized exhibited partial PPARδ activity (23–98%) with EC₅₀ values ranging from 0.007–18.2 μM. Some ligands, such as compound 32, were more potent inhibitors of VDR-mediated transcription with significantly reduced PPARδ activity than GW0742, however, none of the ligands were completely selective for VDR inhibition over PPARδ activation of transcription.

中文翻译：

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基于 GW0742 支架的平行化学方法鉴定新型核受体配体

我们描述了 GW0742 的新型类似物的平行合成，GW0742 是一种过氧化物酶体增殖物激活受体 δ (PPARδ) 激动剂。为此，应用了改进的反应条件，例如固相钯催化的 Suzuki 偶联。此外，生成了基于四唑的化合物作为含羧酸配体 GW0742 的生物等排体。研究了这些新化合物激活 PPARδ 介导的转录的能力以及它们与维生素 D 受体 (VDR) 的交叉反应性，维生素 D 受体 (VDR) 是核受体超家族的另一个成员。我们鉴定了许多毒性低于 GW0742 的强效 PPARδ 激动剂，其中约 65 种合成的化合物表现出部分 PPARδ 活性（23-98%），EC ₅₀值范围为 0.007-18.2 μM。一些配体，例如化合物32，是比 GW0742 更有效的 VDR 介导的转录抑制剂，PPARδ 活性显着降低，然而，没有一个配体对 VDR 抑制比 PPARδ 转录激活具有完全选择性。