Design and synthesis of dual modulators of soluble epoxide hydrolase and peroxisome proliferator-activated receptors.

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la Buscato E, Blocher R, Lamers C, Klingler FM, Hahn S, Steinhilber D, Schubert-Zsilavecz M, Proschak E

Design and synthesis of dual modulators of soluble epoxide hydrolase and peroxisome proliferator-activated receptors.

J Med Chem. 2012 Dec 13;55(23):10771-5. doi: 10.1021/jm301194c. Epub 2012 Nov 19.

PubMed ID

23130964 [ View in PubMed

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Abstract

Metabolic syndrome is a complex condition which often requires the use of multiple medications as a treatment. The resulting problems of polypharmacy are increase in side effects, drug-drug interactions, and its high economic cost. Development of multitarget compounds is a promising strategy to avoid the complications arising from administration of multiple drugs. Modulators of peroxisome proliferator-activated receptors (PPARs) are established agents in the treatment of dyslipidaemia, hyperglycaemia, and insulin resistance. Inhibitors of soluble epoxide hydrolase (sEH) are under evaluation for their use in cardiovascular diseases. In the present study, a series of dual sEH/PPAR modulators containing a pyrrole acidic headgroup and a urea pharmacophore were designed, synthesized, and evaluated in vitro using recombinant enzyme and cell-based assays. Compounds with different activity profiles were obtained which could be used in the treatment of metabolic syndrome.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
{4-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]phenoxy}acetic acid	Peroxisome proliferator-activated receptor delta	EC 50 (nM)	39	N/A	N/A	Details
Pioglitazone	Peroxisome proliferator-activated receptor gamma	EC 50 (nM)	200	N/A	N/A	Details