[Design and synthesis of peroxisome proliferator-activated receptor (PPAR) delta agonists and its implication to the driving force to elicit PPAR delta selectivity].

  title={[Design and synthesis of peroxisome proliferator-activated receptor (PPAR) delta agonists and its implication to the driving force to elicit PPAR delta selectivity].},
  author={Jun-ichi Kasuga and Takuji Oyama and Izumi Nakagome and Atsushi Aoyama and Kumiko Sako and Makoto Makishima and Shuichi Hirono and Kosuke Morikawa and Yuichi Hashimoto and Hiroyuki Miyachi},
  journal={Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan},
  volume={129 6},
A series of 3-(4-alkoxypheny)propanoic acid derivatives was prepared as candidate peroxisome proliferator-activated receptor (PPAR) delta-selective agonists, based on our previously discovered potent human PPARalpha/delta dual agonist TIPP-401 as a lead compound. Structure-activity relationship studies clearly indicated the importance of the chain length of the alkoxy group at the 4-position, and the n-butoxy compound exhibited the most potent PPARdelta transactivation activity and highest… 
2 Citations
Crystal Structures of the Human Peroxisome Proliferator-Activated Receptor (PPAR)α Ligand-Binding Domain in Complexes with a Series of Phenylpropanoic Acid Derivatives Generated by a Ligand-Exchange Soaking Method.
The "ligand-exchange soaking method," which crystallizes the recombinant PPARα ligand-binding domain (LBD) as a complex with intrinsic fatty acids derived from an expression host Escherichia (E.) coli and thereafter replaces them with other higher-affinity ligands by soaking, is developed.


Molecular Modeling Study of Species-Selective Peroxisome Proliferator-Activated Receptor (PPAR) α Agonist; Possible Mechanism(s) of Human PPARα Selectivity of an α-Substituted Phenylpropanoic Acid Derivative (KCL)
In order to investigate the reason why phenylpropanoic acid derivative (KCL), a potent, human peroxisome proliferator-activated receptor (PPAR) α-selective agonist, shows this selectivity, we
Design, synthesis, and evaluation of substituted phenylpropanoic acid derivatives as human peroxisome proliferator activated receptor activators. Discovery of potent and human peroxisome proliferator activated receptor alpha subtype-selective activators.
The identification of potent and human PPARalpha selective optically active alpha-alkylphenylpropanoic acid derivatives, which will be useful not only as pharmacological tools to investigate the physiology and pathophysiology of PPAR alpha but also as candidate drugs for the treatment of altered metabolic homeostasis, such as dyslipidemia, obesity, and diabetes.
Analysis of the Critical Structural Determinant(s) of Species-Selective Peroxisome Proliferator-Activated Receptor Alpha (PPARα)-Activation by Phenylpropanoic Acid-Type PPARα Agonists
Abstract In order to identify the critical structural feature(s) of phenylpropanoic acid-type PPARα agonists, such as KCL, which exhibit human peroxisome proliferator-activated receptor alpha
Design and synthesis of substituted phenylpropanoic acid derivatives as human peroxisome proliferator-activated receptor α/δ dual agonists
A series of phenylpropanoic acids was prepared as candidate dual agonists of peroxisome proliferator-activated receptors (PPAR) alpha and delta. Structure-activity relationship studies indicated that
A human peroxisome-proliferator-activated receptor-gamma is activated by inducers of adipogenesis, including thiazolidinedione drugs.
Cloned a human cognate of the mouse peroxisome-proliferator-activated receptor-gamma (hPPAR gamma) from a human placenta cDNA library suggests a high degree of structural and functional similarity between mouse and human PPAR gamma, and provides evidence for variation in human receptor structure which may result in differential sensitivity to activators.
Differential expression and activation of a family of murine peroxisome proliferator-activated receptors.
The data suggest that tissue-specific responsiveness to peroxisome proliferators, including certain fatty acids, is in part a consequence of differential expression of multiple, pharmacologically distinct PPAR isoforms.
A novel insulin sensitizer acts as a coligand for peroxisome proliferator-activated receptor-alpha (PPAR-alpha) and PPAR-gamma: effect of PPAR-alpha activation on abnormal lipid metabolism in liver of Zucker fatty rats.
The results suggest that PPAR-alpha agonism has a protective effect against abnormal lipid metabolism in liver of obese rats.
A selective peroxisome proliferator-activated receptor δ agonist promotes reverse cholesterol transport
  • W. Oliver, J. Shenk, +12 authors T. Willson
  • Biology, Medicine
    Proceedings of the National Academy of Sciences of the United States of America
  • 2001
The results suggest that PPARδ agonists may be effective drugs to increase reverse cholesterol transport and decrease cardiovascular disease associated with the metabolic syndrome X.
Determination of the Critical Amino Acids Involved in the Peroxisome Proliferator‐Activated Receptor (PPAR) δ Selectivity of Phenylpropanoic Acid‐Derived Agonists
The nuclear receptors (NRs) form a superfamily of liganddependent transcription factors that control diverse aspects of numerous biological processes and systems including reproduction, development, homeostasis, and immune function, and the availability of PPARd knockout animals and selective ACHTUNGTRENNUNGligands prompted us to examine the involvement ofPPARd in fatty acid metabolism, insulin resistance, reverse cholesterol transport, inflammation, and other related processes.
Molecular Cloning, Expression and Characterization of Human Peroxisome Proliferator Activated Receptors γ1 and γ2
The results indicate that the antidiabetic effects of thiazolidinediones in humans are likely to be mediated via binding to and transactivation of PPARγ1 and γ2.