Switching subtype-selectivity: Fragment replacement strategy affords novel class of peroxisome proliferator-activated receptor α/δ (PPARα/δ) dual agonists
Switching subtype-selectivity: Fragment replacement strategy affords novel class of peroxisome proliferator-activated receptor α/δ (PPARα/δ) dual agonists
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切换亚型选择性：片段替换策略提供新型过氧化物酶体增殖物激活受体 α/δ (PPARα/δ) 双重激动剂
DOI：
10.1016/j.bmcl.2017.05.037
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发表时间：
2017
影响因子：
2.7
通讯作者：
Takao Yamaguchi
中科院分区：
文献类型：
--
作者：
Ryuta Shioi;Shogo Okazaki;Tomomi Noguchi-Yachide;Minoru Ishikawa;Makoto Makishima;Yuichi Hashimoto;Takao Yamaguchi
过氧化物酶体增殖物激活受体（Peroxisome proliferator-activated receptors，PPARs）是治疗血脂异常、2型糖尿病、心血管疾病、非酒精性脂肪肝和非酒精性脂肪性肝炎的重要药物靶点，人们一直在努力开发新型的PPARs配体。然而，大多数现有的PPAR配体含有对活性至关重要的羧酸（CA）或噻唑烷二酮（TZD）结构（酸性头基）。我们最近发现了非CA/TZD类的PPARα/δ部分激动剂，其含有与1，2，4-恶二唑环连接的乙酰胺部分和相邻的甲基（“片段a”）。我们假设乙酰胺结构可能与CA/TZD结合口袋相互作用。为了验证这一想法，我们首先用在PPAR激动剂中常见的α-烷氧基-CA结构替换了我们的一种化合物中的片段a。其次，我们用我们的乙酰胺基片段a取代了几种报道的PPAR激动剂的α-烷氧基-CA头部基团。通过基于细胞的报告基因测定来评估所合成的杂合化合物对PPARs（PPARα、PPARγ和PPARδ）的激动活性。所有的杂合分子均显示出PPAR激动活性，但α-烷氧基-CA头基的替换改变了最大功效和亚型特异性。基于乙酰胺的杂合分子对PPARα和PPARδ表现出部分激动作用，而基于α-烷氧基-CA的分子通常对PPARα和PPARγ具有选择性，具有相对较高的激活效率。因此，片段置换策略似乎有希望用于开发新的基于乙酰胺的PPARα/δ双重激动剂。
Peroxisome proliferator-activated receptors (PPARs) are important drug targets for treatment of dyslipidemia, type 2 diabetes, cardiovascular disease, nonalcoholic fatty liver disease and nonalcoholic steatohepatitis, and great efforts have been made to develop novel PPAR ligands. However, most existing PPAR ligands contain a carboxylic acid (CA) or thiazolidinedione (TZD) structure (acidic head group) that is essential for activity. We recently discovered non-CA/TZD class PPARα/δ partial agonists, which contain an acetamide moiety and adjacent methyl group, linked to a 1,2,4-oxadiazole ring (“fragment a”). We hypothesized that the acetamide structure might interact with the CA/TZD-binding pocket. To test this idea, we firstly replaced fragment a in one of our compounds with the α-alkoxy-CA structure often found in PPAR agonists. Secondly, we replaced the α-alkoxy-CA head group of several reported PPAR agonists with our acetamide-based fragment a. The agonistic activities of the synthesized hybrid compounds toward PPARs (PPARα, PPARγ and PPARδ) were evaluated by means of cell-based reporter gene assays. All the hybrid molecules showed PPAR-agonistic activities, but replacement of the α-alkoxy-CA head group altered the maximum efficacy and the subtype-specificity. The acetamide-based hybrid molecules showed partial agonism toward PPARα and PPARδ, whereas the α-alkoxy-CA-based molecules were generally selective for PPARα and PPARγ, with relatively high activation efficacies. Thus, the fragment replacement strategy appears promising for the development of novel acetamide-based PPARα/δ dual agonists.