Institute of Pharmaceutical Chemistry, Goethe University, Max-von-Laue-Strasse 9, D-60438 Frankfurt am Main, Germany.
Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, D-60596 Frankfurt am Main, Germany.
J Med Chem. 2021 Mar 11;64(5):2815-2828. doi: 10.1021/acs.jmedchem.0c02063. Epub 2021 Feb 23.
The metabolic syndrome (MetS) is a constellation of cardiovascular and metabolic symptoms involving insulin resistance, steatohepatitis, obesity, hypertension, and heart disease, and patients suffering from MetS often require polypharmaceutical treatment. PPARγ agonists are highly effective oral antidiabetics with great potential in MetS, which promote adipocyte browning and insulin sensitization. However, the application of PPARγ agonists in clinics is restricted by potential cardiovascular adverse events. We have previously demonstrated that the racemic dual sEH/PPARγ modulator RB394 () simultaneously improves all risk factors of MetS in vivo. In this study, we identify and characterize the eutomer of . We provide structural rationale for molecular recognition of the eutomer. Furthermore, we could show that the dual sEH/PPARγ modulator is able to promote adipocyte browning and simultaneously exhibits cardioprotective activity which underlines its exciting potential in treatment of MetS.
代谢综合征（MetS）是一组涉及胰岛素抵抗、脂肪性肝炎、肥胖、高血压和心脏病的心血管和代谢症状，患有 MetS 的患者通常需要联合多种药物治疗。PPARγ 激动剂是高效的口服抗糖尿病药物，在 MetS 中有很大的应用潜力，可促进脂肪细胞棕色化和胰岛素敏感性。然而，PPARγ 激动剂在临床上的应用受到潜在心血管不良事件的限制。我们之前已经证明，外消旋双 sEH/PPARγ 调节剂 RB394（）在体内同时改善 MetS 的所有危险因素。在这项研究中，我们确定并表征了。我们为外消旋体的分子识别提供了结构依据。此外，我们还表明，这种双重 sEH/PPARγ 调节剂能够促进脂肪细胞棕色化，同时具有心脏保护活性，这突出了其在 MetS 治疗中的令人兴奋的潜力。
