A novel oxyiminoalkanoic acid derivative, TAK-559, activates human peroxisome proliferator-activated receptor subtypes

European Journal of Pharmacology
Junichi SakamotoHidekazu Sawada

Abstract

A novel oxyiminoalkanoic acid derivative, TAK-559, (E)-4-[4-[(5-methyl-2-phenyl-1, 3-oxazol-4-yl)methoxy]benzyloxyimino]-4-phenylbutyric acid, was synthesized as a candidate of a new type of insulin-sensitizing agent. We report here activation of human peroxisome proliferator-activated receptor (hPPAR) subtypes by TAK-559. In a transient transactivation assay, TAK-559 was a potent hPPARgamma1 and hPPARalpha agonist with EC50 values of 31 and 67 nM, respectively. Furthermore, TAK-559 was a partial agonist for hPPARgamma1 with about 68% of maximal activation obtained with rosiglitazone (5-(4-(2-(methyl(2-pyridinyl)amino)ethoxy) benzyl)-1,3-thiazolidine-2,4-dione), a thiazolidinedione derivative, which is known as a PPARgamma agonist. PPARdelta was significantly activated at a high concentration (10 microM) of TAK-559. Competition-binding assays using radiolabeled ligand indicated that the transactivation of all hPPAR subtypes by TAK-559 was due to direct binding of TAK-559 to each subtype. We also demonstrated that TAK-559 acts to recruit the coactivator SRC-1 to each of hPPARgamma1 and hPPARalpha, and to dissociate the corepressor NCoR from each of hPPARgamma1 and hPPARalpha. Taken together, we conclude that TAK-559 is a dual ag...Continue Reading

References

Dec 15, 1995·Cell·D J Mangelsdorf, R M Evans
Apr 29, 1997·Proceedings of the National Academy of Sciences of the United States of America·B M FormanR M Evans
Aug 7, 1998·Atherosclerosis·B Staels, J Auwerx
Sep 2, 1998·Proceedings of the National Academy of Sciences of the United States of America·J WangJ M Liu
May 26, 1999·Proceedings of the National Academy of Sciences of the United States of America·J L OberfieldT M Willson
Feb 26, 2000·Journal of Medicinal Chemistry·T M WillsonB R Henke
Nov 30, 2000·Biochemical and Biophysical Research Communications·J SakamotoH Sawada
Apr 20, 2001·Proceedings of the National Academy of Sciences of the United States of America·W R OliverT M Willson
Jun 4, 2002·The Medical Journal of Australia·Trisha M O'Moore-Sullivan, Johannes B Prins
Oct 28, 2003·Diabetes Care·Carlos LorenzoUNKNOWN San Antonio Heart Study

❮ Previous
Next ❯

Citations

Jan 25, 2007·Expert Opinion on Investigational Drugs·Jerry R Colca
Jul 7, 2015·Journal of Ophthalmology·Su ZhangNan Hu
Feb 23, 2008·Bioorganic & Medicinal Chemistry Letters·Wei WangPeter T W Cheng
Oct 30, 2007·ChemMedChem·Oliver RauManfred Schubert-Zsilavecz
Nov 30, 2006·Pharmacological Reviews·Liliane MichalikWalter Wahli
Nov 10, 2020·Journal of Cardiovascular Pharmacology·Charikleia Kalliora, Konstantinos Drosatos
Jan 21, 2012·Journal of Medicinal Chemistry·Céline PiratPhilippe Chavatte

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.