Open AccessA Novel N-Substituted Valine Derivative with Unique Peroxisome Proliferator-Activated Receptor γ Binding Properties and Biological Activities
Author(s) -
Franck Peiretti,
R. Montanari,
Davide Capelli,
Bernadette Bonardo,
Cécilia Colson,
Ez-Zoubir Amri,
Marina Grimaldi,
Patrick Balaguer,
Keiichi Ito,
Robert G. Roeder,
G. Pochetti,
Jean Michel Brunel
Publication year - 2020
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.0c01555
Subject(s) - chemistry , peroxisome proliferator activated receptor , biochemistry , adipocyte , serine , agonist , receptor , valine , peroxisome , rosiglitazone , phosphorylation , stereochemistry , amino acid , adipose tissue
A proprietary library of novel N -aryl-substituted amino acid derivatives bearing a hydroxamate head group allowed the identification of compound 3a that possesses weak proadipogenic and peroxisome proliferator-activated receptor γ (PPARγ) activating properties. The systematic optimization of 3a , in order to improve its PPARγ agonist activity, led to the synthesis of compound 7j ( N -aryl-substituted valine derivative) that possesses dual PPARγ/PPARα agonistic activity. Structural and kinetic analyses reveal that 7j occupies the typical ligand binding domain of the PPARγ agonists with, however, a unique high-affinity binding mode. Furthermore, 7j is highly effective in preventing cyclin-dependent kinase 5-mediated phosphorylation of PPARγ serine 273. Although less proadipogenic than rosiglitazone, 7j significantly increases adipocyte insulin-stimulated glucose uptake and efficiently promotes white-to-brown adipocyte conversion. In addition, 7j prevents oleic acid-induced lipid accumulation in hepatoma cells. The unique biochemical properties and biological activities of compound 7j suggest that it would be a promising candidate for the development of compounds to reduce insulin resistance, obesity, and nonalcoholic fatty liver disease.