Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 64, Issue 5, Pages 2815-2828Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.0c02063
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Funding
- SGC [1097737]
- AbbVie
- Bayer Pharma AG
- Boehringer Ingelheim
- Canada Foundation for Innovation
- Eshelman Institute for Innovation
- Genome Canada
- Innovative Medicines Initiative (EU/EFPIA)
- Janssen
- Merck KGaA, Germany
- MSD
- Novartis Pharma AG
- Ontario Ministry of Economic Development and Innovation
- Pfizer
- Sao Paulo Research Foundation-FAPESP
- Takeda
- Wellcome
- German Research Foundation (DFG) [PR1405/4-2, SFB 1039, SFB 1177, TE912/2-2, Fi1700/5-1, Fi1700/7-1]
- research funding program LandesOffensive zur Entwicklung Wissenschaftlich-okonomischer Exzellenz (LOEWE) of the State of Hessen
- Research Center for Translational Medicine and Pharmacology TMP
- Frankfurt Cancer Centre (FCI)
- German Cancer Consortium (DKTK)
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Metabolic syndrome is a group of cardiovascular and metabolic symptoms, and patients often require polypharmaceutical treatment. PPAR gamma agonists show potential in treating MetS but are restricted by cardiovascular adverse events. Research has shown that RB394 can improve all risk factors of MetS and exhibits exciting potential in treatment.
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. PPAR gamma agonists are highly effective oral antidiabetics with great potential in MetS, which promote adipocyte browning and insulin sensitization. However, the application of PPAR gamma agonists in clinics is restricted by potential cardiovascular adverse events. We have previously demonstrated that the racemic dual sEH/PPAR gamma modulator RB394 (3) simultaneously improves all risk factors of MetS in vivo. In this study, we identify and characterize the eutomer of 3. We provide structural rationale for molecular recognition of the eutomer. Furthermore, we could show that the dual sEH/PPAR gamma modulator is able to promote adipocyte browning and simultaneously exhibits cardioprotective activity which underlines its exciting potential in treatment of MetS.
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