Structure-Based Design of Dual Partial Peroxisome Proliferator-Activated Receptor γ Agonists/Soluble Epoxide Hydrolase Inhibitors,Journal of Medicinal Chemistry

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Structure-Based Design of Dual Partial Peroxisome Proliferator-Activated Receptor γ Agonists/Soluble Epoxide Hydrolase Inhibitors
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-11-24 , DOI: 10.1021/acs.jmedchem.1c01331
Felix F Lillich ₁ , Sabine Willems ₁ , Xiaomin Ni _{1,

2} , Whitney Kilu ₁ , Carmen Borkowsky ₁ , Mirko Brodsky ₁ , Jan S Kramer ₁ , Steffen Brunst ₁ , Victor Hernandez-Olmos ₃ , Jan Heering ₃ , Simone Schierle ₁ , Roxane-I Kestner ₄ , Franziska M Mayser ₄ , Moritz Helmstädter ₁ , Tamara Göbel ₁ , Lilia Weizel ₁ , Dmitry Namgaladze ₅ , Astrid Kaiser ₁ , Dieter Steinhilber ₁ , Waltraud Pfeilschifter ₄ , Astrid S Kahnt ₁ , Anna Proschak ₁ , Apirat Chaikuad _{1,

2} , Stefan Knapp _{1,

2} , Daniel Merk ₁ , Ewgenij Proschak _{1,

3}

Affiliation

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 in vivo 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.

中文翻译：

双部分过氧化物酶体增殖物激活受体γ激动剂/可溶性环氧化物水解酶抑制剂的基于结构的设计

多种药物方案通常会损害代谢综合征 (MetS) 患者的治疗，这是一种复杂的疾病集群，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) 在各种体内协同抵消 MetS模型和双重 sEH 抑制剂/PPARγ 激动剂在减少与多药治疗相关的问题方面具有巨大潜力。然而，完全激活 PPARγ 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，我们使用结构引导的方法设计了一种双重部分 PPARγ 激动剂/sEH 抑制剂。详尽的结构-活性关系研究导致设计的引线成功优化。一种具有两个目标的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。

更新日期：2021-12-09

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