2. Academic Validation
  3. Design, synthesis, and biological evaluation of novel dual FFA1 and PPARδ agonists possessing phenoxyacetic acid scaffold

Design, synthesis, and biological evaluation of novel dual FFA1 and PPARδ agonists possessing phenoxyacetic acid scaffold

  • Bioorg Med Chem. 2022 Feb 15:56:116615. doi: 10.1016/j.bmc.2022.116615.
Zongtao Zhou 1,  Zongyu Cai 2,  Congzi Zhang 3,  Benhui Yang 2,  Lianru Chen 2,  Yepu He 3,  Luyong Zhang 4,  Zheng Li 5
Affiliations

Affiliations

  • 1 School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR China; Key Laboratory of New Drug Discovery and Evaluation, 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.
  • 2 School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR China.
  • 3 Xianning Central Hospital, The First Affiliated Hospital of Hubei University Of Science And Technology, Xianning 437000, PR China.
  • 4 School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR China; Key Laboratory of New Drug Discovery and Evaluation, 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].
  • 5 School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR China; Key Laboratory of New Drug Discovery and Evaluation, Guangdong Pharmaceutical University, Guangzhou 510006, PR China; National Key Clinical Department (Clinical Pharmacy), The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510006, PR China. Electronic address: [email protected].
PMID: 35051813 DOI: 10.1016/j.bmc.2022.116615
Abstract

The Free Fatty Acid Receptor 1 (FFA1/GPR40) and Peroxisome Proliferator-activated Receptor δ (PPARδ) have been widely considered as promising targets for type 2 diabetes mellitus (T2DM) due to their respective roles in promoting Insulin secretion and improving Insulin sensitivity. Hence, the dual FFA1/PPARδ agonists may exert synergistic effects by simultaneously activating FFA1 and PPARδ. The present study performed systematic exploration around previously reported FFA1 agonist 2-(2-fluoro-4-((2'-methyl-4'-(3-(methylsulfonyl)propoxy)-[1,1'-biphenyl]-3-yl)methoxy)phenoxy)acetic acid (lead compound), leading to the identification of a novel dual FFA1/PPARδ Agonist 2-(2-fluoro-4-((3-(6-methoxynaphthalen-2-yl)benzyl)oxy)phenoxy)acetic acid (the optimal compound), which displayed high selectivity over PPARα and PPARγ. In addition, the docking study provided us with detailed binding modes of the optimal compound in FFA1 and PPARδ. Furthermore, the optimal compound exhibited greater glucose-lowering effects than lead compound, which might attribute to its synergistic effects by simultaneously modulating Insulin secretion and resistance. Moreover, the optimal compound has an acceptable safety profile in the acute toxicity study at a high dose of 500 mg/kg Therefore, our results provided a novel dual FFA1/PPARδ Agonist with excellent glucose-lowering effects in vivo.

Keywords

Dual agonist; FFA1; Glucose-lowering; PPARδ; T2DM.

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