Peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor central to fatty acid and glucose homeostasis. PPARγ is the molecular target for type 2 diabetes mellitus (T2DM) therapeutics TZDs (thiazolidinediones), full agonists of PPARγ with robust antidiabetic properties, which are confounded with significant side effects. Partial agonists of PPARγ, such as INT131 (1), have displayed similar insulin-sensitizing efficacy as TZDs, but lack many side effects. To probe the structure–activity relationship (SAR) of the scaffold 1, we synthesized 14 analogs of compound 1 which revealed compounds with higher transcriptional potency for PPARγ and identification of moieties of the scaffold 1 key to high transcriptional potency. The sulfonamide linker is critical to activity, substitutions at position 4 of the benzene ring A were associated with higher transcriptional activity, substitutions at position 2 aided in tighter packing and activity, and the ring type and size of ring A affected the degree of activity.

中文翻译：

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PPARγ靶向抗糖尿病药的2,4-二氯-N-（3,5-二氯-4-（喹啉-3-基氧基）苯基）苯磺酰胺（INT131）类似物的结构-活性关系

过氧化物酶体增殖物激活受体γ（PPARγ）是脂肪酸和葡萄糖体内稳态的核心核受体。PPARγ是2型糖尿病（T2DM）治疗药物TZD（噻唑烷二酮类）的分子靶标，TZD是具有强大抗糖尿病特性的PPARγ的完全激动剂，具有明显的副作用。PPARγ的部分激动剂，例如INT131（1），已显示出与TZD相似的胰岛素敏感性，但缺乏许多副作用。为了探究支架1的结构-活性关系（SAR），我们合成了化合物1的14个类似物，这些化合物揭示了对PPARγ具有更高转录效力的化合物，并鉴定了支架1的部分高转录潜能的关键。磺酰胺连接子对活性至关重要，苯环A的4位取代与更高的转录活性相关，2位的取代有助于更紧密的包装和活性，并且环A的环类型和大小影响了活性。