Institute of Pharmaceutical Chemistry, Goethe-University, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany.
Structural Genomics Consortium, Buchmann Institute for Molecular Life Sciences, Goethe-University, Max-von-Laue-Str. 15, D-60438 Frankfurt, Germany.
J Med Chem. 2021 Dec 9;64(23):17259-17276. doi: 10.1021/acs.jmedchem.1c01331. Epub 2021 Nov 24.
Polypharmaceutical regimens often impair treatment of patients with metabolic syndrome (MetS), a complex disease cluster, including obesity, hypertension, heart disease, and type II diabetes. Simultaneous targeting of soluble epoxide hydrolase (sEH) and peroxisome proliferator-activated receptor γ (PPARγ) synergistically counteracted MetS in various models, and dual sEH inhibitors/PPARγ agonists hold great potential to reduce the problems associated with polypharmacy in the context of MetS. However, full activation of PPARγ leads to fluid retention associated with edema and weight gain, while partial PPARγ agonists do not have these drawbacks. In this study, we designed a dual partial PPARγ agonist/sEH inhibitor using a structure-guided approach. Exhaustive structure-activity relationship studies lead to the successful optimization of the designed lead. Crystal structures of one representative compound with both targets revealed potential points for optimization. The optimized compounds exhibited favorable metabolic stability, toxicity, selectivity, and desirable activity in adipocytes and macrophages.
多药治疗方案常影响代谢综合征（MetS）患者的治疗，MetS 是一种复杂的疾病群，包括肥胖、高血压、心脏病和 II 型糖尿病。同时靶向可溶性环氧化物水解酶（sEH）和过氧化物酶体增殖物激活受体 γ（PPARγ）在多种模型中协同对抗 MetS，双重 sEH 抑制剂/PPARγ 激动剂具有很大的潜力，可减少 MetS 背景下多药治疗相关的问题。然而，PPARγ 的完全激活会导致与水肿和体重增加相关的液体潴留，而部分 PPARγ 激动剂则没有这些缺点。在这项研究中，我们使用基于结构的方法设计了一种双重部分 PPARγ 激动剂/sEH 抑制剂。广泛的构效关系研究成功优化了设计的先导化合物。与两个靶点的一个代表性化合物的晶体结构揭示了潜在的优化点。优化后的化合物在脂肪细胞和巨噬细胞中表现出良好的代谢稳定性、毒性、选择性和理想的活性。
