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

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Discovery of a Series of 4-Amide-thiophene-2-carboxyl Derivatives as Highly Potent P2Y14 Receptor Antagonists for Inflammatory Bowel Disease Treatment
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-07-03 , 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}

Affiliation

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.

中文翻译：

发现一系列 4-酰胺-噻吩-2-羧基衍生物作为高效 P2Y14 受体拮抗剂，用于治疗炎症性肠病

P2Y ₁₄受体已被证明是 IBD 的潜在靶点。在此，我们基于支架跳跃策略设计并合成了一系列4-酰胺-噻吩-2-羧基衍生物作为新型有效的P2Y ₁₄受体拮抗剂。优化的化合物39 (5-((5-氟吡啶-2-基)氧基)-4-(4-甲基苯甲酰氨基)噻吩-2-羧酸)表现出亚纳摩尔拮抗活性(IC ₅₀ ：0.40nM)。此外，化合物39表现出显着改善的溶解度、肝微粒体稳定性和口服生物利用度。荧光配体结合实验证实39具有与P2Y ₁₄受体的结合能力，分子动力学（MD）模拟揭示了在结合构象中形成了独特的分子内氢键（IMHB）。在实验性结肠炎小鼠模型中，化合物39即使在低剂量下也显示出显着的抗IBD效果。化合物39具有有效的抗 IBD 作用和良好的成药性，可能成为进一步研究的有希望的候选者。此外，这项工作为P2Y ₁₄受体拮抗剂的开发和IBD的治疗策略奠定了坚实的基础。

更新日期：2024-07-03

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