Synthesis and evaluation of an orally available "Y"-shaped biaryl peroxisome proliferator-activated receptor δ agonist

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 2.6 nM. We also synthesized and evaluated enantiospecific R and S isomers of compound 3a to confirm that R isomer (EC₅₀ = 0.7 nM) shows much more potent activity than S isomer (EC₅₀ = 6.1 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.

Keywords: ADMET; Nuclear receptors; PK; PPARδ; Structure-activity relationship (SAR).