Synthesis and evaluation of an orally available "Y"-shaped biaryl peroxisome proliferator-activated receptor δ agonist.
Bioorg Med Chem
; 26(15): 4382-4389, 2018 08 15.
Article
in En
| MEDLINE
| ID: mdl-30054191
ABSTRACT
In this study, we designed and synthesized several novel "Y"-shaped biaryl PPARδ agonists. Structure-activity relationship (SAR) studies demonstrated that compound 3a was the most active agonist with an EC50 of 2.6â¯nM. We also synthesized and evaluated enantiospecific R and S isomers of compound 3a to confirm that R isomer (EC50â¯=â¯0.7â¯nM) shows much more potent activity than S isomer (EC50â¯=â¯6.1â¯nM). Molecular docking studies between the PPAR ligand binding domain and enantiospecific R and S isomers of compound 3a were performed. In vitro absorption, distribution, metabolism, excretion, and toxicity (ADMET) and in vivo PK profiles show that compound 3a possesses superior drug-like properties including good bioavailability. Our overall results clearly demonstrate that this orally administrable PPARδ agonist 3a is a viable drug candidate for the treatment of various PPARδ-related disorders.
Key words
Full text:
1
Database:
MEDLINE
Main subject:
Biphenyl Compounds
/
PPAR delta
/
Acetates
Limits:
Animals
/
Humans
Language:
En
Year:
2018
Type:
Article