Goethe University Frankfurt, Institute of Pharmaceutical Chemistry, Max-von-Laue-Str. 9, D-60438, Frankfurt, Germany.
Project Group Translational Medicine and Pharmacology TMP, Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Theodor-Stern-Kai 7, D-60596, Frankfurt, Germany.
Sci Rep. 2018 Sep 10;8(1):13554. doi: 10.1038/s41598-018-31833-4.
Gout is the most common arthritic disease in human but was long neglected and therapeutic options are not satisfying. However, with the recent approval of the urate transporter inhibitor lesinurad, gout treatment has experienced a major innovation. Here we show that lesinurad possesses considerable modulatory potency on peroxisome proliferator-activated receptor γ (PPARγ). Since gout has a strong association with metabolic diseases such as type 2 diabetes, this side-activity appears as very valuable contributing factor to the clinical efficacy profile of lesinurad. Importantly, despite robustly activating PPARγ in vitro, lesinurad lacked adipogenic activity, which seems due to differential coactivator recruitment and is characterized as selective PPARγ modulator (sPPARγM).
痛风是人类最常见的关节疾病，但长期以来被忽视，治疗选择并不令人满意。然而，随着尿酸转运体抑制剂 lesinurad 的最近获批，痛风治疗经历了重大创新。在这里，我们表明 lesinurad 对过氧化物酶体增殖物激活受体 γ (PPARγ) 具有相当大的调节作用。由于痛风与 2 型糖尿病等代谢疾病密切相关，这种副作用似乎是 lesinurad 临床疗效的一个非常有价值的贡献因素。重要的是，尽管 lesinurad 在体外强烈激活 PPARγ，但它缺乏脂肪生成活性，这似乎是由于不同的共激活因子募集所致，并被表征为选择性 PPARγ 调节剂（sPPARγM）。
