Discovery of the first-in-class dual PPARδ/γ partial agonist for the treatment of metabolic syndrome

Zheng Li; Qiang Ren; Zongtao Zhou; Zongyu Cai; Bin Wang; Jing Han; Luyong Zhang

doi:10.1016/j.ejmech.2021.113807

Discovery of the first-in-class dual PPARδ/γ partial agonist for the treatment of metabolic syndrome

Eur J Med Chem. 2021 Dec 5:225:113807. doi: 10.1016/j.ejmech.2021.113807. Epub 2021 Aug 25.

Authors

Zheng Li¹, Qiang Ren², Zongtao Zhou³, Zongyu Cai³, Bin Wang³, Jing Han⁴, Luyong Zhang⁵

Affiliations

¹ School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Key Laboratory of New Drug Discovery and Evaluation of Ordinary Universities of Guangdong Province, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China. Electronic address: [email protected].
² School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Key Laboratory of New Drug Discovery and Evaluation of Ordinary Universities of Guangdong Province, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Guangzhou Key Laboratory of Construction and Application of New Drug Screening Model Systems, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China.
³ School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China.
⁴ School of Chemistry and Chemical Engineering, Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional Materials, Jiangsu Normal University, Xuzhou, 221116, PR China.
⁵ School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Key Laboratory of New Drug Discovery and Evaluation of Ordinary Universities of Guangdong Province, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Guangzhou Key Laboratory of Construction and Application of New Drug Screening Model Systems, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, 210009, PR China. Electronic address: [email protected].

PMID: 34455359
DOI: 10.1016/j.ejmech.2021.113807

Abstract

The peroxisome proliferator-activated receptors (PPARs) exert vital function in the regulation of energy metabolism, which were considered as promising targets of metabolic syndrome. Until now, PPARδ/γ dual agonist is rarely reported, and thereby the pharmacologic action of PPARδ/γ dual agonist is still unclear. In this study, we identified a dual PPARδ/γ partial agonist 6 (ZLY06) based on the cyclization strategy of PPARα/δ dual agonist GFT505. ZLY06 revealed excellent pharmacokinetic profiles suitable for oral medication. Moreover, ZLY06 markedly improved glucolipid metabolism without weight gain, and alleviated fatty liver by promoting the β-oxidation of fatty acid and inhibiting hepatic lipogenesis. In contrast, weight gain and hepatic steatosis were observed in Rosiglitazone, a widely used PPARγ full agonist. All of these results indicated that ZLY06 exhibits potential benefits on metabolic syndrome, while no adverse effects related to PPARγ full agonist.

Keywords: Diabetes; Fatty liver; Insulin resistance; Metabolic syndrome; PPAR.

MeSH terms

Animals
Diabetes Mellitus, Experimental / chemically induced
Diabetes Mellitus, Experimental / drug therapy*
Diabetes Mellitus, Experimental / metabolism
Diet, High-Fat
Dose-Response Relationship, Drug
Drug Discovery*
Male
Metabolic Syndrome / chemically induced
Metabolic Syndrome / drug therapy*
Metabolic Syndrome / metabolism
Mice
Mice, Inbred C57BL
Molecular Structure
Organic Chemicals / chemical synthesis
Organic Chemicals / chemistry
Organic Chemicals / pharmacology*
PPAR delta / agonists*
PPAR delta / metabolism
PPAR gamma / agonists*
PPAR gamma / metabolism
Rats
Rats, Sprague-Dawley
Streptozocin
Structure-Activity Relationship

Substances

Organic Chemicals
PPAR delta
PPAR gamma
ZLY06
Streptozocin