Design, synthesis and anti-inflammatory evaluation of 3-amide benzoic acid derivatives as novel P2Y14 receptor antagonists

Zhenguo Zhang; Kun Hao; Hanwen Li; Ran Lu; Chunxiao Liu; Mengze Zhou; Baiyang Li; Zibo Meng; Qinghua Hu; Cheng Jiang

doi:10.1016/j.ejmech.2019.111564

Design, synthesis and anti-inflammatory evaluation of 3-amide benzoic acid derivatives as novel P2Y₁₄ receptor antagonists

Eur J Med Chem. 2019 Nov 1:181:111564. doi: 10.1016/j.ejmech.2019.111564. Epub 2019 Jul 26.

Authors

Zhenguo Zhang¹, Kun Hao², Hanwen Li³, Ran Lu¹, Chunxiao Liu³, Mengze Zhou³, Baiyang Li⁴, Zibo Meng⁴, Qinghua Hu⁵, Cheng Jiang⁶

Affiliations

¹ Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Tongjiaxiang 24, Nanjing, 210009, China; Department of Medicinal Chemistry, China Pharmaceutical University, Tongjiaxiang 24, Nanjing, 210009, China.
² State Key Laboratory of Natural Medicines, China Pharmaceutical University, Tongjiaxiang 24, Nanjing, 210009, China.
³ Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Tongjiaxiang 24, Nanjing, 210009, China.
⁴ Department of Medicinal Chemistry, China Pharmaceutical University, Tongjiaxiang 24, Nanjing, 210009, China.
⁵ Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Tongjiaxiang 24, Nanjing, 210009, China. Electronic address: huqh@cpu.edu.cn.
⁶ Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Tongjiaxiang 24, Nanjing, 210009, China; Department of Medicinal Chemistry, China Pharmaceutical University, Tongjiaxiang 24, Nanjing, 210009, China. Electronic address: jc@cpu.edu.cn.

PMID: 31376563
DOI: 10.1016/j.ejmech.2019.111564

Abstract

The P2Y₁₄ receptor (P2Y₁₄R) plays a key role in the modulation of inflammatory process, but very few classes of antagonists have been reported. A series of 3-amide benzoic acid derivatives were identified as novel and potent P2Y₁₄R antagonists. The most potent antagonist, 16c, showed comparable activity (IC₅₀ = 1.77 nM) to PPTN, the most potent P2Y₁₄R antagonist reported. Compound 16c demonstrated dramatically improved aqueous solubility and excellent metabolic stability in rat and human microsomes. Investigation of the anti-inflammatory effect of 16c was performed in MSU treated THP-1 cells by flow cytometry, Western Blot and immunofluorescence labeling technology, which exhibited that 16c might be a promising candidate for further research.

Keywords: 3-Amide benzoic acid derivatives; Antagonist; Anti-inflammation; G protein-coupled receptor; P2Y(14) receptor.

MeSH terms

Amides / chemical synthesis
Amides / chemistry
Amides / pharmacology
Animals
Anti-Inflammatory Agents / chemical synthesis
Anti-Inflammatory Agents / chemistry*
Anti-Inflammatory Agents / pharmacology*
Benzoic Acid / chemical synthesis
Benzoic Acid / chemistry*
Benzoic Acid / pharmacology*
Cell Line
Drug Design
Humans
Molecular Docking Simulation
Purinergic P2 Receptor Antagonists / chemical synthesis
Purinergic P2 Receptor Antagonists / chemistry*
Purinergic P2 Receptor Antagonists / pharmacology*
Rats
Receptors, Purinergic P2 / metabolism

Substances

Amides
Anti-Inflammatory Agents
P2Y14 receptor, human
Purinergic P2 Receptor Antagonists
Receptors, Purinergic P2
Benzoic Acid