Structure-Based Design of Dual Partial Peroxisome Proliferator-Activated Receptor. Agonists/Soluble Epoxide Hydrolase Inhibitors

被引：15

作者：

Lillich, Felix F. ^{[1
]}

Willems, Sabine ^{[1
]}

Ni, Xiaomin ^{[1
,2
]}

Kilu, Whitney ^{[1
]}

Borkowsky, Carmen ^{[1
]}

Brodsky, Mirko ^{[1
]}

Kramer, Jan S. ^{[1
]}

Brunst, Steffen ^{[1
]}

Hernandez-Olmos, Victor ^{[3
]}

Heering, Jan ^{[3
]}

Schierle, Simone ^{[1
]}

Kestner, Roxane-, I ^{[4
]}

Mayser, Franziska M. ^{[4
]}

Helmstaedter, Moritz ^{[1
]}

Goebel, Tamara ^{[1
]}

Weizel, Lilia ^{[1
]}

Namgaladze, Dmitry ^{[5
]}

Kaiser, Astrid ^{[1
]}

Steinhilber, Dieter ^{[1
]}

Pfeilschifter, Waltraud ^{[4
]}

Kahnt, Astrid S. ^{[1
]}

Proschak, Anna ^{[1
]}

Chaikuad, Apirat ^{[1
,2
]}

Knapp, Stefan ^{[1
,2
]}

Merk, Daniel ^{[1
]}

Proschak, Ewgenij ^{[1
,3
]}

机构：

[1] Goethe Univ, Inst Pharmaceut Chem, D-60438 Frankfurt, Germany

[2] Goethe Univ, Buchmann Inst Mol Life Sci, Struct Genom Consortium, D-60438 Frankfurt, Germany

[3] Fraunhofer Inst Translat Med & Pharmacol ITMP, D-60596 Frankfurt, Germany

[4] Goethe Univ, Univ Hosp Frankfurt, Dept Neurol, D-60590 Frankfurt, Germany

[5] Goethe Univ, Univ Hosp Frankfurt, Inst Biochem 1, D-60590 Frankfurt, Germany

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2021年 / 64卷 / 23期

关键词：

X-RECEPTOR; PPAR-GAMMA; MODULATOR; DISCOVERY; BINDING; LIGAND; METABOLISM; ACIDS;

D O I：

10.1021/acs.jmedchem.1c01331

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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. (PPAR.) synergistically counteracted MetS in various in vivo models, and dual sEH inhibitors/PPAR. agonists hold great potential to reduce the problems associated with polypharmacy in the context of MetS. However, full activation of PPAR. leads to fluid retention associated with edema and weight gain, while partial PPAR. agonists do not have these drawbacks. In this study, we designed a dual partial PPAR. agonist/sEH inhibitor using a structureguided 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.

引用

页码：17259 / 17276

页数：18

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