Discovery of a Series of 4-Amide-thiophene-2-carboxyl Derivatives as Highly Potent P2Y14 Receptor Antagonists for Inflammatory Bowel Disease Treatment

  • J Med Chem. 2024 Jul 3. doi: 10.1021/acs.jmedchem.4c00699.
Yu-Hang Wang  1  2 ,  Chun-Xiao Liu  1  3 ,  Yi-Han Zhang  1  2 ,  Ya-Lian Yang  1  3 ,  Yan Zhao  1  3 ,  Lu Han  1  3 ,  Qian-Qian Wang  1  2 ,  Wen Xiao  1  2 ,  Qing-Hua Hu  1  3  4 ,  Zhen-Hua Ding  1  2 ,  Meng-Ze Zhou  1  3 ,  Cheng Jiang  1  2
Affiliations
  • 1. School of Pharmacy, China Pharmaceutical University, Nanjing 211198, P. R. China.
  • 2. Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 211198, P. R. China.
  • 3. State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, P. R. China.
  • 4. School of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, P. R. China.
PMID: 38959216 DOI: 10.1021/acs.jmedchem.4c00699
Abstract

The P2Y14 receptor has been proven to be a potential target for IBD. Herein, we designed and synthesized a series of 4-amide-thiophene-2-carboxyl derivatives as novel potent P2Y14 receptor antagonists based on the scaffold hopping strategy. The optimized compound 39 (5-((5-fluoropyridin-2-yl)oxy)-4-(4-methylbenzamido)thiophene-2-carboxylic acid) exhibited subnanomolar antagonistic activity (IC50: 0.40 nM). Moreover, compound 39 demonstrated notably improved solubility, liver microsomal stability, and oral bioavailability. Fluorescent ligand binding assay confirmed that 39 has the binding ability to the P2Y14 receptor, and molecular dynamics (MD) simulations revealed the formation of a unique intramolecular hydrogen bond (IMHB) in the binding conformation. In the experimental colitis mouse model, compound 39 showed a remarkable anti-IBD effect even at low doses. Compound 39, with a potent anti-IBD effect and favorable druggability, can be a promising candidate for further research. In addition, this work lays a strong foundation for the development of P2Y14 receptor antagonists and the therapeutic strategy for IBD.

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