In vivo imaging reveals selective peroxisome proliferator activated receptor modulator activity of the synthetic ligand 3-(1-(4-chlorobenzyl)-3-t-butylthio-5-isopropylindol-2-yl)-2,2-dimethylpropanoic acid (MK-886).
We report here the finding of a new pharmacological activity of a well known antagonist of peroxisome proliferator-activated receptors (PPARs). PPARs belong to the family of nuclear receptors playing a relevant role in mammalian physiology and are currently believed to represent a major target for the development of innovative drugs for metabolic and inflammatory diseases. In the present study, the application of reporter animal technology was instrumental to obtain the global pharmacological profiling indispensable to unraveling 3-(1-(4-chlorobenzyl)-3-t-butylthio-5-isopropylindol-2-yl)-2,2-dimethylpropanoic acid (MK-886)-selective PPAR modulator (SPPARM) activity not underlined by previous traditional, cell-based studies. The results of this study, demonstrating the usefulness of reporter mice, may open new avenues for the development of innovative drugs for cardiovascular, endocrine, neural, and skeletal systems characterized by limited side effects.
Biserni
Andrea
A
Center of Excellence on Neurodegenerative Diseases, Department of Pharmacological Sciences, University of Milan, Via Balzaretti 9, 20133 Milan, Italy.
Giannessi
Fabio
F
Sciarroni
Anna Floriana
AF
Milazzo
Ferdinando Maria
FM
Maggi
Adriana
A
Ciana
Paolo
P
D000818:Animals; D004353:Drug Evaluation, Preclinical; D005786:Gene Expression Regulation / Q000187:drug effects; D017930:Genes, Reporter; D007211:Indoles / Q000494:pharmacology*; D008024:Ligands; D008156:Luciferases / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D047493:PPAR alpha / Q000819:agonists / Q000037:antagonists & inhibitors; D047495:PPAR gamma / Q000819:agonists / Q000037:antagonists & inhibitors; D047492:Peroxisome Proliferator-Activated Receptors / Q000378:metabolism*; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology; D020218:Response Elements; D015398:Signal Transduction / Q000187:drug effects; D013737:Testis / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D014018:Tissue Distribution / Q000187:drug effects; D051598:Whole Body Imaging / Q000379:methods*; D002722:Chlorobenzenes
D007211:Indoles; D008024:Ligands; D008156:Luciferases; D047493:PPAR alpha; D047495:PPAR gamma; D047492:Peroxisome Proliferator-Activated Receptors; D011743:Pyrimidines; C060893:MK-886; D002722:Chlorobenzenes; C006253:pirinixic acid