PPARδ activator

Inventors

Ogura, Toshihiko • HAKOSHIMA, Toshio • MIYASAKA, Kota • Kubo, Atsushi

Assignees

Japan Science and Technology Agency

Abstract

The present invention provides a PPARδ activator containing a novel PPARδ agonist (peroxisome proliferator-activated receptor δ) as an active ingredient, and an exercise tolerance-improving agent containing the same as an active ingredient. The present invention is a PPARδ activator containing a guanidine derivative or a biguanidine derivative as an active ingredient, wherein the PPARδ activator activates transcriptional activity of PPARδ, and the guanidine derivative and the biguanidine derivative are capable of fitting within a PPARδ ligand binding pocket in a state where a guanidino group or a biguanidino group forms a hydrogen bond with amino acid residues corresponding to each of the 413th histidine, 287th histidine, 253rd threonine and the 437th tyrosine of human PPARδ, among amino acid residues constituting an interior surface of the ligand binding pocket; and is an exercise tolerance-improving agent containing the PPARδ activator as an active ingredient.

Core Innovation

The invention relates to a PPARδ agonist that activates transcriptional activity of PPARδ. The PPARδ agonist comprises a guanidine derivative as an active ingredient, where the guanidine derivative is defined by specific compound formulas including (A-1) to (A-4) and (B-1) to (B-3). The provided description includes experimental evidence that metformin binds PPARδ and functions as a PPARδ agonist.

The description reports binding specificity and functional activation in the PPARδ ligand-binding domain. Biophysical measurements, truncation mutants, docking, and molecular dynamics indicate that guanidine or biguanidine derivatives bind within the PPARδ ligand-binding pocket, and functional assays show activation of PPARδ transcriptional activity, increased PPARδ/PGC1α complex formation, target gene expression, and recruitment to promoters.

The invention further includes structural evidence from a PPARδ ligand-binding domain complex with metformin, which defines a Y-shaped ligand-binding pocket with arms I to III and describes hydrogen-bond interactions with Thr253, His287, His413, and Tyr437. The description also characterizes closure and an active conformation involving AF-2 (H12), and includes protein/ligand complex atomic-coordinate tables and computational analyses of binding behavior.

Claims Coverage

The independent claim defines 1 principal inventive concept: using a guanidine derivative represented by formulas (A-1) to (A-4) and (B-1) to (B-3) as an active ingredient to activate PPARδ transcriptional activity. Dependent claims further specify binding-pocket interactions and intended uses.

Across the independent claim and its dependents, the inventive features center on a PPARδ agonist with a guanidine derivative defined by formulas (A-1) to (A-4) and (B-1) to (B-3), including a specified guanidino-group hydrogen-bond interaction with His413, His287, Thr253, and Tyr437, and specified uses as an exercise tolerance-improving agent or in pharmaceutical compositions for treating or preventing disease, including diabetes, obesity, cardiomyopathy, and liver fibrosis, and for immunotherapy.

Stated Advantages

Documented Applications